BR112018010118B1 - CXCR2 INHIBITORS - Google Patents

Abstract

cxcr2 inhibitors. The present invention relates to compounds which are provided as cxcr2 inhibitors, having structure (i).

Description

CROSS REFERENCES TO RELATED ORDERS

[0001] This application is an application claiming the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 62/257,529, filed on November 19, 2015, which is incorporated herein by reference in its entirety.

STATEMENT ON RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0002] NOT APPLICABLE.

REFERENCE TO A "SEQUENCE LISTING", A TABLE OR A COMPUTER PROGRAM LISTING ATTACHMENT SUBMITTED ON COMPACT DISK

[0003] NOT APPLICABLE.

BACKGROUND OF THE INVENTION

[0004] Chemokines are chemostatic cytokines that are released by a wide variety of cells, to attract cells, such as leukocytes (including macrophages, T cells, eosinophils, basophils, neutrophils and myeloid-derived suppressor cells) and endothelial cells to sites of inflammation and tumor growth. There are two main classes of chemokines, the CXC-chemokines and the CC-chemokines. The class depends on whether the first two cysteines are adjacent (CC-chemokines) or are separated by a single amino acid (CXC-chemokines). There are currently at least 17 known CXC-chemokines, which include, but are not limited to, CXCL1 (GROα), CXCL2 (GROβ), CXCL3 (GROY), CXCL4 (PF4), CXCL5 (ENA-78), CXCL6 (GCP-2, CXCL7 (NAP-2), CXCL8 (IL-8, NAP-1), CXCL9 (MIG), and CXCL10 (IP-10) There are currently at least 28 known CC chemokines, which include, but are not limited to, CCL2 (MCP-). 1), CCL3 (MIP-1α), CCL4 (MIP-1 β), CCL5 (RANTES), CCL7 (MCP-3), CCL8 (MCP-2), CCL-11 (eotaxin-1) and CCL20 (MIP- 3α).Individual members of the chemokine families are known to be bound by at least one chemokine receptor, with CXC-chemokines generally bound by members of the CXCR class of receptors, and CC-chemokines by members of the CCR class of receptors. For example, CXCL8/IL-8 is bound by the CXCR1 and CXCR2 receptors.

[0005] Since CXC-chemokines generally promote the accumulation and activation of neutrophils, these chemokines are implicated in a wide variety of acute and chronic inflammatory disorders, such as psoriasis, rheumatoid arthritis, radiation-induced fibrotic lung disease, autoimmune bullous dermatoses (AIBD), chronic obstructive pulmonary disease (COPD), and ozone-induced airway inflammation (see, Baggiolini et al., FEBS Lett. 307:97 (1992); Miller et al., Crit. Rev. Imunol 12:17 (1992); .Respir Dis. 146:427 (1992); . Genet. Syndr. Genet. S3:005 (2013), Miller et al., Br. , 72:282 (2011)).

[0006] A subset of CXC chemokines, which contain the ELR motif (ELR-CXC), has been implicated in the induction of tumor angiogenesis (new blood vessel growth). They include the CXCR2 ligand chemokines: CXCL-1, CXCL2, CXCL3, CXCL5 and (Strieter et al. JBC 270: 27348-27357 (1995)). Some ELR-CXC CXCR2 ligand chemokines are exacerbating agents during ischemic stroke (Connell et al., Neurosci. Lett., 15:30111 (2015). All of these chemokines are believed to exert their actions by binding to CXCR2. Thus, its angiogenic activity is due to its binding and activation of CXCR2 expressed on the surface of vascular endothelial cells (ECs) in adjacent vessels.

[0007] Many different types of tumors are known to produce ELR-CXC chemokines, and the production of these chemokines correlates with a more aggressive phenotype (Inoue et al. Clin Cancer Res 6:2104-2119 (2000)) and poor prognosis (Yoneda et. al. J Nat Cancer Inst 90:447-454 (1998)). ELR-CXC chemokines are potent chemostatic factors for EC chemotaxis, they likely induce chemotaxis of endothelial cells to their production site in the tumor. This may be a critical step in the induction of tumor angiogenesis. CXCR2 inhibitors will inhibit the angiogenic activity of ELR-CXC chemokines and therefore block tumor growth. This antitumor activity has been demonstrated for antibodies to CXCL8 (Arenberg et al. J Clin Invest 97:2792-2802 (1996)), ENA-78 (Arenberg et al. J Clin Invest 102:465-72 (1998)), and CXCL1 (Haghneg-ahdar et al. J. Leukoc Biology 67:53-62 (2000)).

[0008] Many tumor cells express CXCR2 and tumor cells can thus stimulate their own growth by secreting ELR-CXC chemokines. Thus, in addition to reducing angiogenesis within tumors, CXCR2 inhibitors can directly inhibit tumor cell growth.

[0009] CXCR2 is commonly expressed by myeloid-derived suppressor cells (MDSC) within the tumor microenvironment. MDSC are implicated in the suppression of tumor immune responses, and migration of MDSC in response to CXCR2-ligand chemokines is most likely responsible for the attraction of these cells to tumors. (see Marvel and Gabrilovich, J. Clin. Invest. 13:1 (2015) and Mackall et al., Sci. Trans. Med. 6:237 (2014). Thus, CXCR2 inhibitors may reverse suppressive processes and thus allow immune cells to reject the tumor more effectively. Indeed, blocking the activation of CXC-chemokine receptors has proven useful as a combination therapy with checkpoint inhibitors in suppressing tumor growth, suggesting that CXCR2 blockade may also enhance tumor rejection in combination with other antitumor therapies, including but not limited to vaccines or traditional cytotoxic chemotherapies (see Highfill et al., Science Translational Medicine, 6:237 (2014)).

[00010] Therefore, CXC-chemokine receptors represent promising targets for the development of new anti-inflammatory and antitumor agents.

[00011] There remains, therefore, a need for compounds that are capable of modulating the activity of CXC-chemokine receptors. For example, conditions associated with an increase in the production of IL-8 (which is responsible for chemotaxis of neutrophil and T cell subsets at the inflammatory site and tumor growth) would benefit from compounds that are inhibitors of IL-8 receptor binding.

BRIEF SUMMARY OF THE INVENTION

[00012] Provided herein, in one aspect, are compounds having formula (I),

[00013] In formula (I) above, and herein, R1 and R2 are each independently selected members of the group consisting of H, halogen, CN, C1-4 alkyl, C1-4 alkoxy and C1-4 haloalkyl ; R3a is a member selected from the group consisting of methyl, ethyl, propyl, isopropyl, trifluoromethyl, CH2CF3 and CF2CF3; R3b is a member selected from the group consisting of H and D; R4 is a member selected from the group consisting of H, C1-8 alkyl, -Y and C1-4alkylene-Y; wherein Y is aryl or heteroaryl, and each R4 is optionally substituted by one to four substituents selected from the group consisting of halogen, -CN, -CO2Ra, -CONRaRb, -C(O)Ra, -OC(O)NRaRb , NRaC(O)Rb, NRaC(O)2 Rc, -NRaC(O)NRaRb, -NRaRb, -ORa, -S(O)2NRaRb, - NRaS(O)2Rb, and -Rc, where each Ra and Rb is independently selected from hydrogen, C1-4 alkyl, C1-4 hydroxyalkyl and C1-4 haloalkyl, Rc is selected from C1-4 alkyl, C1-4 hydroxyalkyl and C1-4 haloalkyl; R5a and R5b are each independently selected members of the group consisting of H, halogen, C1-4 alkyl, C1-4 alkoxy and CN; R6a and R6b are each independently selected members of the group consisting of H, C1-4 alkyl, C1-4 hydroxyalkyl and C1-4 haloalkyl; or, optionally, R6a and R6b are taken together to form oxo (=O); X is CH or N; or any salts, solvates, hydrates, N-oxides, tautomers or rotamers thereof.

[00014] The compounds provided herein are useful for selectively binding and inhibiting the activity of CXCR2, and treating diseases that are dependent, at least in part, on the activity of CXCR2. Accordingly, the present invention provides, in other aspects, compositions containing one or more of the above-indicated compounds in admixture with a pharmaceutically acceptable excipient.

[00015] In yet another aspect, provided herein are methods for treating various diseases, further discussed herein, comprising administering to an individual in need of such treatment a therapeutically effective amount of a compound of the above formula for a sufficient period of time. to treat the disease.

[00016] In yet another aspect, methods of diagnosing the disease in an individual are provided here. In these methods, the compounds provided herein are administered in labeled form to an individual, followed by diagnostic imaging to determine the presence or absence of CXCR2. In a related aspect, a disease diagnosis method is performed by contacting a tissue or blood sample with a labeled compound as provided herein and determining the presence, absence, or amount of CXCR2 in the sample.

[00017] In some embodiments, an amount of a chemotherapeutic agent or radiation is administered to the subject prior to, subsequent to, or in combination with the compounds provided herein. In some embodiments, the amount is subtherapeutic when the chemotherapeutic agent or radiation is administered alone.

BRIEF DESCRIPTION OF THE DRAWINGS

[00018] Figures 1A-1J provide structures and biological activity for the compounds described in this document.

DETAILED DESCRIPTION OF THE INVENTION

[00019] Before the present invention is further described, it should be understood that the invention is not limited to the particular embodiments set forth herein, and it should also be understood that the terminology used here is for the purpose of describing only particular embodiments, and It is not intended to be limiting.

[00020] When a range of values is provided, it is understood that each intermediate value, up to the tenth of a unit of the lower limit, unless the context clearly indicates otherwise, between the upper and lower limit of that range and any other value intermediate or stated in said range, is covered by the invention. The lower and upper limits of these smaller ranges may independently be included in the smaller ranges, and individuals at any limit specifically excluded in the stated range are also covered within the scope of the invention. When a stated range includes one or both limits, ranges excluding both included limits are also included in the invention. Unless otherwise defined, all technical and scientific terms in this document have the same meaning commonly understood by one skilled in the art to which this invention belongs.

[00021] It should be noted that, as used here and in the appended claims, the singular forms "a", "an", "the" and "a" include the plural referents, unless the context clearly indicates otherwise. It should further be noted that claims may be written to exclude any optional elements. Accordingly, such statement is intended to serve as a preliminary basis for the use of such exclusive terminology, such as "solely", "only" and the like, in connection with the enumeration of claim elements, or for the use of a limitation "negative".

General

[00022] The present invention derives from the discovery that compounds of formula I act as potent and selective antagonists of the CXCR2 receptor. The compounds have anti-inflammatory activity in vivo and have superior pharmacokinetic properties. Thus, the compounds provided herein are useful in pharmaceutical compositions, methods for treating CXCR2-mediated diseases and as controls in assays for the identification of competitive CXCR2 antagonists.

Abbreviation and Definitions

[00023] The term "alkyl", alone or as part of another substituent, means, unless otherwise indicated, a straight or branched chain hydrocarbon radical, having the designated number of carbon atoms (i.e., C1-8 means one to eight carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like. The term "alkenyl" refers to an unsaturated alkyl group having one or more double bonds. Similarly, the term "alkynyl" refers to an unsaturated alkyl group having one or more triple bonds. Examples of such unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3- propynyl, 3-butynyl, and higher isomers and homologs. The term "cycloalkyl" refers to hydrocarbon rings having the indicated number of ring atoms (e.g., C3-6 cycloalkyl) and being fully saturated or having, at most, one double bond between ring vertices. "Cycloalkyl" also refers to bicyclic and polycyclic hydrocarbon rings, such as, for example, bicyclo[2,2,1] heptane, bicyclo[2,2,2]octane, etc. The term "cycloalkenyl" refers to a cycloalkyl group having at least one double bond between ring vertices. Examples of cycloalkenyl are cyclopentenyl and cyclohexenyl. The term "spirocycloalkyl" refers to a cycloalkyl group in which a single ring vertex is bonded to two other non-hydrogen portions of the molecule. A spirocycloalkyl substituent is one in which two carbon atoms of an alkylene chain (typically, the termini of the alkylene chain) are attached to the same carbon atom in the remainder of the molecule. The term "heterocycloalkyl" refers to a cycloalkyl group containing one to five heteroatoms selected from N, O, and S, in which the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) is(are) optionally quaternized. The heterocycloalkyl may be a monocyclic, bicyclic or polycyclic ring system. Non-limiting examples of heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S, S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetridrothiophene, quinuclidine and the like. A heterocycloalkyl group can be linked to the rest of the molecule through a carbon ring or a heteroatom.

[00024] The term "alkylene" alone or as part of another substituent means a divalent radical derived from an alkane, as exemplified by -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A "lower alkyl" or "lower alkylene" is a shorter-chain alkyl or alkylene group that typically has four or fewer carbon atoms. Similarly, "alkenylene" and "alkynylene" refer to unsaturated forms of "alkylene" having double or triple bonds, respectively.

[00025] As used herein, a wavy line, "~~", which intersects a single, double, or triple bond in any chemical structure presented herein, represents the point of attachment of the single, double, or triple bond to the remainder of the molecule. Additionally, a bond that extends toward the center of a ring (e.g., a phenyl ring) indicates bonding at any of the available ring vertices. One skilled in the art will understand that various substituents shown to be attached to a ring will occupy ring vertices that provide stable compounds and are otherwise sterically compatible.

[00026] The terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are used in their conventional sense and refer to those alkyl groups linked to the rest of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively. Furthermore, for dialkylamino groups, the alkyl moieties may be the same or different and may also be combined to form a 3-7 membered ring with the nitrogen atom to which each is attached. Accordingly, a group represented as -NRaRb is intended to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl and the like.

[00027] The terms "halo" or "halogen", alone or as part of another substituent, mean, unless otherwise indicated, a fluorine, chlorine, bromine or iodine atom. Additionally, terms such as "haloalkyl" include monohaloalkyl and polyhaloalkyl. For example, the term "C 1-4 haloalkyl" is used to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl and the like.

[00028] The term "aryl" means, unless otherwise indicated, a polyunsaturated hydrocarbon group, typically aromatic, which may be a single ring or several rings (up to three rings) that fuse or are covalently linked. The term "heteroaryl" refers to aryl groups (or rings) that contain one to five heteroatoms selected from N, O, and S, in which the nitrogen and sulfur atoms are optionally oxidized, and the atom(s) ) of nitrogen is(are) optionally quaternized. A heteroaryl group can be linked to the rest of the molecule through a heteroatom. Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl, while non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinolinol, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl , benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, , indazolyl, pteridinyl, imidazolyl , triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl and the like. Substituents for each of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below,

[00029] The term "arylalkyl" is intended to include those radicals in which an aryl group is attached to an alkyl group (for example, benzyl, phenethyl and the like). Similarly, the term "heteroaryl-alkyl" is intended to include those radicals in which a heteroaryl group is attached to an alkyl group (e.g., pyridylmethyl, thiazolylethyl, and the like).

[00030] The above terms (e.g., "alkyl", "aryl" and "heteroaryl"), in some embodiments, will include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[00031] Substituents for alkyl radicals (including those groups generally referred to as alkylene, alkenyl, alkynyl and cycloalkyl) can be a variety of groups selected from: - halogen, -OR', -NR'R", -SR' , -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', - CONR'R", -OC(O)NR'R", -NR"C (O)R', -NR'-C(O)NR"R"', -NR"C(O)2R', -NH-C(NH2) =NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', - S(O)2R', -S(O)2 NR'R", -NR'S(O)2R", -CN and - NO2 in a number ranging from zero to (2 m'+1), where m' is the total number of carbon atoms in such radical R', R" and R"', each independently, refer to. hydrogen, C1-8 unsubstituted alkyl, unsubstituted aryl, aryl substituted by 1-3 halogens, C1-8 unsubstituted alkyl, C1-8 alkoxy or C1-8 thioalkoxy groups or unsubstituted aryl-C1-4 alkyl groups When. R' and R" are bonded to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6- or 7-membered ring. For example, -NR'R" is intended to include 1-pyrrolidinyl and 4-morpholinyl.

[00032] Similarly, substituents for the aryl and heteroaryl groups are varied and are generally selected from: -halogen, -OR', -OC(O)R', -NR'R", -SR', - R', -CN, -NO2, -CO2R', -CONR'R", -C(O)R', -OC (O)NR'R", -NR"C(O)R', -NR" C(O)2R', -NR'-C(O)NR"R"', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR ', -S(O)R', -S(O)2R', -S(O)2NR'R", -NR'S(O)2R", -N3, perfluoro(C1-C4)alkoxy, and perfluoro( C1- C4)alkyl, in a number ranging from zero to the total number of open valences in the aromatic ring system and in which R', R" and R"' are independently selected from hydrogen, C1-8 alkyl, C1-8; haloalkyl, C3-6 cycloalkyl, C2-8 alkenyl, C2-8 alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-C1-4 alkyl, and unsubstituted aryloxy-C1-4 alkyl. each of the above aryl substituents bonded to a ring atom by an alkylene ether of 1-4 carbon atoms.

[00033] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)-(CH2)q-U-, where T and U are independently -NH-, -O -, -CH2- or a single bond, and q is an integer from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be substituted with a substituent of the formula -A-(CH2)r-B- , where A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'- or a bond simple, and r is an integer from 1 to 3. One of the single bonds of the new ring thus formed can optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be substituted with a substituent of the formula -(CH2)s-X- (CH2)t-, wherein s and t are independently integers from 0 to 3, and is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituent R’ in -NR’- and -S(O)2NR’- is selected from hydrogen or unsubstituted C1-6 alkyl.

[00034] As used herein, the term "heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).

[00035] When a variable (e.g., R1 or Ra) occurs more than once in any constituent, its definition upon each occurrence is independent of its definition upon all other occurrences. Additionally, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

[00036] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds that are prepared with relatively non-toxic bases or acids, depending on the particular substituents found in the compounds described herein. When the compounds provided herein contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, pure or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When the compounds provided herein contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of that compound with a sufficient amount of the desired acid, either pure or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids, such as hydrochloric, hydrobromic, nitric, carbonic, monohydrocarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydroiodic or phosphorous and the like, as well as salts derived from relatively non-toxic organic acids, such as acetic, propionic, isobutyric, malic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic and similar. Also included are salts of amino acids, such as arginate and the like, and salts of organic acids, such as glucuronic or galactonic acids and the like. (see, for example, Berge, S.M., et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds provided herein contain both basic and acidic functionalities that allow the compounds to be converted into base or acid addition salts.

[00037] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the original compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for purposes of the present invention.

[00038] In addition to salt forms, the present invention provides compounds that are in a prodrug form. The prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds provided herein. Furthermore, prodrugs can be converted into the compounds provided herein through chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted into the compounds provided herein when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[00039] Certain compounds provided in this document may exist in unsolvated forms, as well as in solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are intended to be within the scope of the present invention. Certain compounds provided herein may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

[00040] Certain compounds provided in this document have asymmetric carbon atoms (optical centers) or double bonds; Racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present invention. In some embodiments, the compounds of the invention are present in an enantiomerically enriched form, wherein the amount of excess enantiomer for a given enantiomer is calculated by conventional methods. The preparation of enantiomerically enriched forms is also well known in the art and can be carried out using, for example, chiral resolution through chromatography or through chiral salt formation. When a particular stereochemical representation is shown herein, it is intended to refer to that form of the compound in stereochemistry as shown and substantially free of the other isomer. "Substantially free from" another isomer indicates at least an 80/20 ratio of the two isomers, more preferably, 90/10 or 95/5 or more. In some embodiments, one of the isomers will be present in an amount of at least 99%. Additionally, different conformers are contemplated by the present invention, as well as different rotamers. Conformers are conformational isomers that can differ by rotations about one or more a-bonds. Rotamers are conformers that differ by rotation about only a single bond. Furthermore, the compounds provided herein may also contain unnatural ratios of atomic isotopes in one or more of the atoms constituting such compound. Therefore, in some embodiments, the compounds of the invention are present in isotopically enriched form. Unnatural proportions of an isotope can be defined as ranging from the amount found in nature to an amount equivalent to 100% of the atom in question. For example, the compounds may incorporate radioactive isotopes, such as, for example, tritium (3H), iodine-125 (125I), or carbon-14 (14C), or non-radioactive isotopes, such as deuterium (2H) or carbon-13 (13C). These isotopic variations may provide additional utilities to those described elsewhere in this application. For example, isotopic variants of the compounds of the invention may find additional utility, including, but not limited to, as diagnostic and/or imaging reagents, or as cytotoxic/radiotoxic therapeutic agents. Additionally, isotopic variants of the compounds of the invention may have altered pharmacokinetic and pharmacodynamic characteristics that may contribute to increasing safety, tolerance or efficacy during treatment. All isotopic variations of the compounds provided herein, whether radioactive or not, are within the scope of the present invention. Certain compounds provided herein are shown in a tautomeric form (e.g., a pyridone form), which is understood by one skilled in the art to include the form shown as well as the other tautomeric form (e.g., a hydroxyl-pyridine ).

[00041] "CXCR2" refers to CXC Chemokine Receptor 2, also known as CD128, IL8RB and IL8 type B receptor, whose gene is encoded on human chromosome 2q35 and is a known receptor for CXCL1, CXCL2, CXCL3, CXCL5, CXCL6 , CXCL7 and CXCL8 (see Murphy, P.M., Annu. Rev. Imunol. 12:593 (1994) and Zlotnik & Yoshie, Immunity, 12:127 (2000)).

[00042] The terms "patient" or "subject" are used interchangeably to refer to a human or non-human animal (e.g., a mammal).

[00043] The terms "administration", "administer" and the like, as they apply, for example, to an individual, cell, tissue, organ or biological fluid, refer to the contact of, for example, a CXCR2 inhibitor, a pharmaceutical composition comprising it or a diagnostic agent to the individual, cell, tissue, organ or biological fluid. In the context of a cell, administration includes contact (e.g., in vitro or ex vivo) of a reagent with the cell, as well as contact of a reagent with a fluid, wherein the fluid is in contact with the cell.

[00044] The terms "treat", "treating", "treatment" and the like refer to a course of action (such as administration of a CXCR2 inhibitor or a pharmaceutical composition containing it) initiated following a disease, disorder or condition , or such a symptom, has been diagnosed, observed and the like, so as to eliminate, reduce, suppress, mitigate or improve, whether temporarily or permanently, at least one of the underlying causes of a disease, disorder or condition afflicting an individual, or at least one of the symptoms associated with a disease, disorder or condition that afflicts an individual. Thus, treatment includes inhibition (e.g., stopping the development or further development of the disease, disorder or condition or clinical symptoms associated therewith) of an active disease.

[00045] The term "in need of treatment", as used herein, refers to a judgment made by a doctor or other caregiver that an individual needs or will benefit from treatment. This judgment is made based on a variety of factors that are within the domain of the doctor or caregiver's expertise.

[00046] The terms "prevent", "preventing", "prevention" and the like refer to a course of action (such as administration of a CXCR2 inhibitor or a pharmaceutical composition containing it) initiated in a manner (e.g., before of the onset of a disease, disorder, condition or symptom thereof) to prevent, suppress, inhibit or reduce, temporarily or permanently, an individual's risk of developing a disease, disorder, condition or the like (as determined, for example, by the absence of clinical symptoms) or delay the onset of these, generally, in the context of an individual predisposed to having a particular disease, disorder or condition. In certain cases, the terms also refer to slowing the progression of the disease, disorder or condition or inhibiting the progression thereof into a harmful or otherwise undesirable state.

[00047] The term "in need of prevention", as used herein, refers to a judgment made by a physician or other caregiver that an individual needs or will benefit from preventive care. This judgment is made based on a variety of factors that are within the domain of the doctor or caregiver's expertise.

[00048] The expression "therapeutically effective amount" refers to the administration of an agent to an individual, alone or as part of a pharmaceutical composition, whether in a single dose or as part of a series of doses, in an amount capable of presenting any detectable positive effect on any symptom, aspect or characteristic of a disease, disorder or condition when administered to the individual. The therapeutically effective amount can be determined by measuring relevant physiological effects, and can be adjusted in relation to the dosage regimen and diagnostic analysis of the subject's condition, and the like. For example, measuring the serum level of a CXCR2 inhibitor (or, for example, a metabolite thereof) at a specified time post-administration may be indicative that a therapeutically effective amount was used.

[00049] The phrase "in an amount sufficient to effect a change" means that there is a detectable difference between a level of an indicator measured before (e.g., a baseline level) and after administration of a particular therapy. Indicators include any objective parameter (e.g., serum concentration) or subjective parameter (e.g., an individual's sense of well-being).

[00050] The term "small molecules" refers to a chemical compound having a molecular weight that is less than about 10 kDa, less than about 2 kDa, or less than about 1 kDa. Small molecules include, but are not limited to, inorganic molecules, organic molecules, organic molecules containing an inorganic component, molecules comprising a radioactive atom, and synthetic molecules. Therapeutically, a small molecule may be more permeable to cells, less susceptible to degradation, and less likely to trigger an immune response than large molecules.

[00051] The terms "inhibitors" and "antagonists" or "activators" and "agonists" refer to inhibitory or activating molecules, respectively, for example, for the activation of, for example, a ligand, receptor, cofactor , gene, cell, tissue or organ. Inhibitors are molecules that decrease, block, prevent, delay activation, inactivate, desensitize or down-regulate, for example, a gene, protein, ligand, receptor or cell. Activators are molecules that enhance, activate, facilitate, enhance activation, sensitize, upregulate, for example, a gene, protein, ligand, receptor or cell. An inhibitor can also be defined as a molecule that reduces, blocks or inactivates a constitutive activity. An "agonist" is a molecule that interacts with a target to cause or promote an increase in activation of the target. An "antagonist" is a molecule that opposes the action(s) of an agonist. An antagonist prevents, reduces, inhibits or neutralizes the activity of an agonist, and an antagonist may also prevent, inhibit or reduce the constitutive activity of a target, for example, a target receptor, even where there is no identified agonist.

[00052] The terms "modulate", "modulation" and the like refer to the ability of a molecule (e.g., an activator or an inhibitor) to increase or decrease the function or activity of CXCR2, directly or indirectly. A modulator may act alone or may use a cofactor, for example, a protein, metal ion, or small molecule. Examples of modulators include small molecule compounds and other bio-organic molecules. Several libraries of small molecule compounds (e.g., combinatorial libraries) are commercially available and can serve as a starting point for identifying a modulator. The person skilled in the art is able to develop one or more assays (e.g., biochemical or cell-based assays) in which such compound libraries can be analyzed to identify one or more compounds having the desired properties; From there, the knowledgeable medical chemist is able to optimize one or more of these compounds, for example, by synthesizing and evaluating analogues and derivatives thereof. Synthetic and/or molecular modeling studies can also be used to identify an Activator.

[00053] The "activity" of a molecule can describe or refer to the binding of the molecule to a ligand or a receptor; to catalytic activity; the ability to stimulate gene expression or cell signaling, differentiation or maturation; antigenic activity; modulating the activities of other molecules; and the like. The term "proliferative activity" encompasses an activity that promotes, is necessary for, or is specifically associated with, for example, normal cell division, as well as cancers, tumors, dysplasia, cellular transformation, metastasis, and angiogenesis.

EMBODIMENTS OF THE INVENTION A. COMPOUNDS

[00054] Provided herein, in one aspect, are compounds having formula (I),

[00055] In formula (I) above, and herein, R1 and R2 are each independently selected members of the group consisting of H, halogen, CN, C1-4 alkyl, C1-4 alkoxy and C1-4 haloalkyl ; R3a is a member selected from the group consisting of methyl, ethyl, propyl, isopropyl, trifluoromethyl, CH2CF3 and CF2CF3; R3b is a selected member of the group consisting of H and D; R4 is a member selected from the group consisting of H, C1-8 alkyl, -Y and C1-4alkylene-Y; wherein Y is aryl or heteroaryl, and each R4 is optionally substituted by one to four substituents selected from the group consisting of halogen, -CN, -CO2Ra, -CONRaRb, -C(O)Ra, -OC(O)NRaRb , NRaC (O)Rb, -NRaC(O)2 Rc, -NRaC(O)NRaRb, -NRaRb, -ORa, -S(O)2NRaRb, - NRaS(O)2Rb, and -Rc, where each Ra and Rb is independently selected from hydrogen, C1-4 alkyl, C1-4 hydroxyalkyl and C1-4 haloalkyl, Rc is selected from C1-4 alkyl, C1-4 hydroxyalkyl and C1-4 haloalkyl; R5a and R5b are each independently selected members of the group consisting of H, halogen, C1-4 alkyl, C1-4 alkoxy and CN; R6a and R6b are each independently selected members of the group consisting of H, C1-4 alkyl, C1-4 hydroxyalkyl and C1-4 haloalkyl; or, optionally, R6a and R6b are taken together to form oxo (=O); X is CH or N; or any salts, solvates, hydrates, N-oxides, tautomers or rotamers thereof.

[00056] Selected modalities are those in which (1) R1 is selected from H, Cl and CH3; or (2) R2 is H; or (3) R3a is ethyl or isopropyl; or (4a) R3b is H; or (4b) R3b is D; or (5) X is CH; or (6) each of R5a and R5b is independently selected from H, Cl and F; or (7) each of R6a and R6b is independently selected from H and C1-4 alkyl; or (8) R4 is C1-8 alkyl, optionally substituted by -halogen, -CN, -CO2Ra, -CONRaRb, -C(O)Ra, -OC(O)NRaRb, -NRaC(O)Rb, -NRaC( O)2 Rc, -NRaC(O)NRaRb, -NRaRb, -ORa, -S(O)2NRaRb, and -NRaS (O)2Rb. Combinations of two or more, three or more, four or more, or five or more of modalities (1) to (8) are also contemplated as additionally selected modalities.

[00057] In additionally selected embodiments, compounds are provided having the formula (Ia): wherein R1 is selected from the group consisting of Cl and CH3; R3b is selected from the group consisting of H and D; R4 is a member selected from the group consisting of H and C1-8 alkyl, wherein the C1-8 alkyl is optionally substituted by -CONRaRb, -OC(O)NRaRb, -NRaC(O) Rb, -NRaC( O)2Rc, -NRaRb, or -ORa, wherein each Ra and Rb is independently selected from hydrogen, C1-4 alkyl, C1-4 hydroxyalkyl and C1-4 haloalkyl, and Rc is selected from C1-4 alkyl, C1-4 hydroxyalkyl and C1-4 haloalkyl; R5a and R5b are each independently selected members of the group consisting of H, F, Cl and CH3; R6a and R6b are each independently selected members of the group consisting of H, C1-4 alkyl, C1-4 hydroxyalkyl and C1-4 haloalkyl; or, optionally, R6a and R6b are taken together to form oxo (=O); or any salts, solvates, hydrates, N-oxides or rotamers thereof.

[00058] Within formula (Ia), additionally selected modalities are those in which R3b is H; R4 is H or CH3; R5a is H, F or Cl; R5b is H, F, Cl; R6a and R6b are independently selected from the group consisting of H and CH3, or are taken together to form oxo (=O).

[00059] Within formula (Ia), still other selected modalities are those in which R3b is D; R4 is H or CH3; R5a is H, F or Cl; R5b is H, F, Cl; R6a and R6b are independently selected from the group consisting of H and CH3, or are taken together to form oxo (=O).

[00060] In other selected embodiments, compounds are provided having the formula (Ib): wherein R1 is selected from the group consisting of Cl and CH3; R3b is selected from the group consisting of H and D; R4 is a member selected from the group consisting of H and C1-8 alkyl, wherein the C1-8 alkyl is optionally substituted by -CONRaRb, -OC(O)NRaRb, -NRaC(O) Rb, -NRaC( O)2Rc, -NRaRb, or -ORa, wherein each Ra and Rb is independently selected from hydrogen, C1-4 alkyl, C1-4 hydroxyalkyl and C1-4 haloalkyl, and Rc is selected from C1-4 alkyl, C1-4 hydroxyalkyl and C1-4 haloalkyl; R5a and R5b are each independently selected members of the group consisting of H, F, Cl and CH3; R6a and R6b are each independently selected members of the group consisting of H, C1-4 alkyl, C1-4 hydroxyalkyl and C1-4 haloalkyl; or, optionally, R6a and R6b are taken together to form oxo (=O); or any salts, solvates, hydrates, N-oxides or rotamers thereof.

[00061] Within formula (Ib), additionally selected embodiments are those wherein R3b is H; R4 is H or CH3; R5a is H, F or Cl; R5b is H, F, Cl; R6a and R6b are independently selected from the group consisting of H and CH3, or are considered together to form oxo (=O).

[00062] Within formula (Ib), still other selected modalities are those in which R3b is D; R4 is H or CH3; R5a is H, F or Cl; R5b is H, F, Cl; R6a and R6b are independently selected from the group consisting of H and CH3, or are taken together to form oxo (=O).

[00063] In another selected group of embodiments, the compound is selected from those provided in the examples below or in Table 1.

[00064] In each of the selected embodiments, the observed compounds may be present in a pharmaceutically acceptable salt or hydrate form.

[00065] In some embodiments, a compound or a pharmaceutically acceptable salt thereof is provided selected from the group consisting of:

[00066] Furthermore, for those compounds shown above without stereochemistry, the present invention also refers to chiral forms of each of the compounds, as well as enantiomerically enriched forms of the observed compounds. Enantiomerically enriched forms can be prepared using chiral chromatography according to well-known methods practiced in the art or, for example, by chiral resolution with a chiral salt form. In some embodiments, the enantiomeric excess of an enantiomerically enriched form is at least 10%, 20%, 30%, 40%, 50%, 60% or more. In still other embodiments, an enantiomerically enriched form is provided which is at least 70%, 80%, 90%, 95%, or more.

Compound Preparation

[00067] Certain compounds of the invention can be prepared following the methodology described in the Examples section of this document. In addition, the syntheses of certain intermediate compounds useful in the preparation of compounds of the invention are also described.

B. Compositions

[00068] In addition to the compounds provided above, compositions for modulating CXCR2 activity in humans and animals will typically contain a pharmaceutical carrier or diluent.

[00069] The term "composition", as used herein, is intended to encompass a product that comprises the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from the combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable", it is understood that the vehicle, diluent or excipient must be compatible with the other ingredients of the formulation and not harmful to its recipient.

[00070] Pharmaceutical compositions for administering the compounds of the present invention can be conveniently presented in unit dosage form and can be prepared by any methods well known in the art of pharmacy and drug administration. All methods include the step of associating the active ingredient with the carrier that constitutes one or more accessory ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately associating the active ingredient with a liquid carrier or a finely divided solid carrier or, if necessary, molding the product into the desired formulation. In the pharmaceutical composition, the active object compound is included in an amount sufficient to produce the desired effect on the disease process or condition.

[00071] Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible granules or powders, emulsions and self-emulsions as described in the Patent Application of USA 2002-0012680, hard or soft capsules, syrups, elixirs, solutions, mouth plaster, oral gel, chewing gum, chewable tablets, effervescent powder and effervescent tablets. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, antioxidants. and preservative agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with pharmaceutically acceptable non-toxic excipients that are suitable for tablet manufacturing. Such excipients may be, for example, inert diluents such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example PVP, cellulose, PEG, starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. Tablets may be uncoated or coated, enteric or otherwise, by techniques known to delay disintegration and absorption in the gastrointestinal tract and thus provide sustained action over a longer period. For example, a delay material such as glyceryl monostearate or glyceryl distearate can be employed. They may also be coated by the techniques described in U.S. Patent Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for controlled release.

[00072] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules, wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil. Furthermore, emulsions can be prepared with a water-immiscible ingredient, such as oil, and stabilized with surfactants, such as monodiglycerides, PEG esters and the like.

[00073] Aqueous suspensions contain active materials in mixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; Dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with aliphatic chain alcohols. long, for example, heptadecaethyleneoxyketanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, for example, ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[00074] Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, for example, peanut oil, olive oil or sesame oil or coconut oil, or in a mineral oil, such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, solid paraffin or cetyl alcohol. Sweetening agents, such as those set out above, and flavoring agents can be added to provide a palatable oral preparation. Such compositions can be preserved by the addition of an antioxidant, such as ascorbic acid.

[00075] Dispersible granules and powders suitable for preparing an aqueous suspension by adding water provide the active ingredient in mixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

[00076] The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying agents may be: naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya, lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.

[00077] Syrups and elixirs can be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and coloring agents. Oral solutions can be prepared in combination with, for example, cyclodextrin, PEG and surfactants.

[00078] Pharmaceutical compositions can be in the form of a sterile injectable aqueous or oily suspension. This suspension may be formulated in accordance with the known art using the suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally acceptable non-toxic diluent or solvent, for example, as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. Furthermore, sterile and fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectables.

[00079] The compounds provided in this document can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at normal temperatures, but liquid at rectal temperatures and, therefore, will melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols. Furthermore, the compounds can be administered through ocular delivery via solutions or ointments. Furthermore, transdermal delivery of said compounds can be carried out using iontophoretic patches and the like. For topical use, creams, ointments, jellies, solutions or suspensions, etc. containing the compounds provided herein are employed. As used herein, topical application is also intended to include the use of mouthwashes and gargles.

[00080] The compounds of the present invention can also be coupled to a carrier that is a polymer suitable as target drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol or polyethylene-oxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the invention can be coupled to a carrier which is a class of biodegradable polymers useful for achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, acid butyric polyhydroxy, polyorthoesters, polyacetals, polydihydropyrans, polyacrylacrylates and cross-linked or amphipathic block copolymers of hydrogels. Semipermeable polymers and polymer matrices can be formed into molded articles, such as valves, stents, tubes, prostheses, and the like.

[00081] A pharmaceutical composition comprising a compound of the present invention is provided. In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of a cytotoxic chemotherapy, antitumor or anticancer vaccines, anti-immunocytokine therapies, immunocytokine therapies, chimeric antigen receptor (CAR) T-cell receptors, gene transfer and checkpoint inhibitors. In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of: drugs that block the activity of CTLA-4 (CD152), PD-1 (CD279), PDL-1 (CD274), TIM-3, LAG-3 (CD223), VISTA, KIR, NKG2A, BTLA, PD-1H, TIGIT, CD96, 4-1BB (CD137), 4-1BBL (CD137L), GARP, CSF-1R, A2AR, CD73, CD47, tryptophan 2,3-dioxygenase (TDO) or indoleamine 2,3 dioxygenase (IDO), and agonists of OX40, GITR, 4-1BB, ICOS, STING or CD40.

C. Methods of Use

[00082] Although it is not desired to be bound by any particular theory, it is considered that the compounds and compositions provided herein provide a therapeutic effect by inhibiting the CXCR2 receptor. Therefore, the compounds and compositions provided herein can be used in the treatment or prevention of diseases or disorders in a mammal, in which inhibition of the CXCR2 receptor would provide a therapeutic effect.

[00083] Another aspect of the invention is the use of a compound, as provided herein, and/or the pharmaceutically acceptable salt and/or a prodrug thereof alone or in combination with other medicaments or active ingredients as to produce a medicament for the treatment or prophylaxis of a chemokine-mediated disease, in which the chemokine binds to a CXCR2 receptor.

[00084] In this sense, methods directed to the use of a compound of formula I and/or a pharmaceutically acceptable salt and/or a prodrug thereof alone or in combination with other medicines or active ingredients such as for the production of a medicament for the treatment or prophylaxis of rheumatoid arthritis, chronic obstructive pulmonary syndrome, adult or acute respiratory distress syndrome, asthma, atherosclerosis, renal or myocardial ischemia/reperfusion injury, ischemia/reperfusion injury of peripheral limb, inflammatory bowel disease, ulcerative colitis, Crohn's disease, meconium aspiration syndrome, atopic dermatitis, cystic fibrosis, psoriasis, psoriatic arthritis, multiple sclerosis, angiogenesis, restenosis, osteoarthritis, osteoporosis, septic shock, endotoxic shock, gram sepsis -negative, toxic shock syndrome, stroke, glomerulonephritis, thrombosis, graft vs. graft reaction. Host, allograft rejections, transplant reperfusion injury, early transplant rejection, acute inflammation, Alzheimer's disease, malaria, respiratory viruses, herpes viruses, hepatitis viruses, HIV, viruses associated with Kaposi's sarcoma, meningitis, gingivitis, herpes encephalitis, CNS vasculitis, traumatic brain injury, cerebral ischemia/reperfusion injury, migraine, CNS tumors, subarachnoid hemorrhage, post-surgical trauma, interstitial pneumonitis, hypersensitivity, crystal-induced arthritis, acute and chronic pancreatitis, hepatic ischemia/reperfusion injury, acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis, uveitis, polymyositis, vasculitis, acne, gastric and duodenal ulcers, intestinal ischemia/reperfusion injury, celiac disease, esophagitis, glossitis, rhinitis, obstruction of airways, airway hyperresponsiveness, bronchiolitis, bronchiolitis obliterans, bronchiolitis obliterans with organizing pneumonia, bronchiectasis, chronic bronchitis, cor pulmonae, dyspnea, emphysema, hypercapnia, hyperinflation, hyperoxia-induced inflammation, hypoxemia, hypoxia, lung injury due to chemo/reperfusion, pulmonary fibrosis, pulmonary hypertension, right ventricular hypertrophy, peritonitis associated with continuous ambulatory peritoneal dialysis, granulocytic ehrlichiosis, sarcoidosis, small airway disease, ventilation-perfusion incompatibility, wheezing, colds, gout, alcoholic liver disease, lupus , burn therapy, periodontitis, premature labor, cough, pruritus, multiple organ dysfunction, trauma, sprains, bruises, release of unwanted hematopoietic stem cells, angiogenic eye disease, ocular inflammation, retinopathy or prematurity, diabetic retinopathy , macular degeneration with the preferred wet type and corneal neovascularization, tumor angiogenesis, cancer and metastasis.

[00085] In particular, the invention further relates to the use of a compound of formula I and/or a pharmaceutically acceptable salt and/or a prodrug thereof alone or in combination with other medicaments or active ingredients to produce a medicament for the treatment or prophylaxis of chronic and acute inflammatory diseases, such as atherosclerosis, ischemia/reperfusion injuries, chronic obstructive pulmonary disease, asthma and rheumatoid arthritis, chemokine-mediated diseases (such as, but not limited to, IL-8, GRO-α , GRO-β, GRO-Y, NAP-2, ENA-78, or GCP-2) which include adult respiratory distress syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, atopic dermatitis, cystic fibrosis, psoriasis , dermatitis, multiple sclerosis, angiogenesis, restenosis, osteoarthritis, septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome, stroke, glomerulonephritis, thrombosis, graft-versus-host reaction, allograft rejections xerto, Alzheimer's disease, malaria, viral infections, traumatic brain injury, pulmonary fibrosis and cancer.

[00086] In some embodiments, the compounds and compositions of the invention are administered to an individual having cancer. In some cases, CXCR2 inhibitors are administered to treat cancer, for example, carcinomas, gliomas, mesotheliomas, melanomas, lymphomas, leukemias (including acute lymphocytic leukemias), adenocarcinomas, breast cancer, ovarian cancer, colon cancer of the uterus, glioblastoma, leukemia, lymphoma, prostate cancer and Burkitt's lymphoma, head and neck cancer, colon cancer, colorectal cancer, non-small cell lung cancer, small cell lung cancer, esophageal cancer, cancer stomach cancer, pancreatic cancer, hepatobiliary cancer, bladder cancer, small intestine cancer, rectal cancer, kidney cancer, kidney cancer, bladder cancer, prostate cancer, penile cancer, urethral cancer, testicular cancer, breast cancer cervix, vaginal cancer, uterine cancer, ovarian cancer, thyroid cancer, parathyroid cancer, adrenal cancer, pancreatic endocrine cancer, carcinoid cancer, bone cancer, skin cancer, retinoblastomas, Hodgkin's lymphoma, non-Hodgkin's lymphoma (see Cancer: Principles And Practice (DeVita, VT et al. eds 1997) for additional cancers); as well as neuronal and brain dysfunction, such as Alzheimer's disease, multiple sclerosis and demyelinating diseases; hypertensive disorders, such as pulmonary arterial hypertension; kidney dysfunction; kidney dysfunction; rheumatoid arthritis; allograft rejection; atherosclerosis (and high cholesterol levels); asthma; glomerulonephritis; contact dermatitis; inflammatory bowel disease; colitis; psoriasis; reperfusion injury; as well as other disorders and diseases described in this document. In some embodiments, the individual does not have Kaposi's sarcoma, multicentric Castleman's disease, or AIDS-associated primary effusion lymphoma.

[00087] In some embodiments, a method of treating a CXCR2-mediated condition or disease in an individual in need thereof is provided, said method comprising administering an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention to said individual. In some embodiments, the CXCR2-mediated disease is an acute or chronic inflammatory disorder. In some embodiments, the CXCR2-mediated acute or chronic inflammatory disorder is selected from the group consisting of psoriasis, rheumatoid arthritis, radiation-induced fibrotic lung disease, autoimmune bullous dermatitis (AIBD), chronic obstructive pulmonary disease, and airway inflammation induced by ozone.

[00088] In some embodiments, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is used to treat cancer alone or in combination with one or more other anticancer therapies. In some embodiments, a compound of the present invention, or a pharmaceutically acceptable salt thereof, is used to treat cancer in combination with one or more of a cytotoxic chemotherapy, an anticancer vaccine, antitumor vaccines, an anti-immunocytokine or immunocytokine therapy, and chimeric antigen receptor (CAR) T cell receptors, gene transfer therapy. In some embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof is used to treat cancer in combination with one or more checkpoint inhibitors. In some embodiments, a compound of the present invention is used to treat cancer in combination with one or more of an anticancer therapy selected from the group consisting of drugs that block the activity of CTLA-4 (CD152), PD-1 (CD279). ), PDL-1 (CD274), TIM-3, LAG-3 (CD223), VISTA, KIR, NKG2A, BTLA, PD-1H, TIGIT, CD96, 4-1BB (CD137), 4-1BBL (CD137L), GARP, CSF-1R, A2AR, CD73, CD47, tryptophan 2,3-dioxygenase (TDO) or indoleamine 2,3 dioxygenase (IDO), and agonists of OX40, GITR, 4-1BB, ICOS, STING or CD40.

[00089] In some embodiments, the compounds of the invention, or a pharmaceutically acceptable salt and/or a prodrug thereof, or compositions of the invention are administered to treat melanoma, glioblastoma, esophageal tumor, nasopharyngeal carcinoma, uveal melanoma, lymphoma, lymphocytic lymphoma, primary CNS lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, prostate cancer, castration-resistant prostate cancer, chronic myelocytic leukemia, Kaposi's sarcoma fibrosarcoma, liposarcoma , chondrosarcoma, osteogenic sarcoma, angiosarcoma, lymphangiosarcoma, synovioma, meningioma, leiomyosarcoma, rhabdomyosarcoma, soft tissue sarcoma, sarcoma, sepsis, biliary tumor, basal cell carcinoma, thymus neoplasm, thyroid gland cancer, parathyroid gland cancer , uterine cancer, adrenal gland cancer, liver infection, Merkel cell carcinoma, nerve tumor, centrofollicular lymphoma, colon cancer, Hodgkin's disease, non-Hodgkin's lymphoma, leukemia, chronic or acute leukemias including acute myeloid leukemia , chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, ovarian tumor, myelodysplastic syndrome, cutaneous or intraocular malignant melanoma, renal cell carcinoma, small cell lung cancer, lung cancer, mesothelioma, cancer breast, squamous non-small cell lung cancer (SCLC), non-squamous NSCLC, colorectal cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic carcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, squamous cell carcinoma of the head and neck cancer, head or neck cancer, gastrointestinal tract, stomach cancer, bone cancer, skin cancer, rectal cancer, cancer of the anal region, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix , carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the urethra, cancer of the penis, cancer of the bladder, cancer of the kidney, cancer of the urethra, carcinoma of the renal pelvis, central nervous system (CNS) neoplasm, tumor angiogenesis, vertebral axis tumor, brainstem glioma, pituitary adenoma, squamous cell cancer, abestosis, carcinoma, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchogenic carcinoma, renal cell carcinoma, carcinoma transitional cell, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, pleomorphic adenoma, hepatic cell papilloma, renal tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma and/or fibroma .

[00090] Other disorders involving problematic or unwanted angiogenesis include rheumatoid arthritis; psoriasis; angiogenic ocular diseases, e.g., diabetic retinopathy, retinopathy of prematurity, macular degeneration, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia, rubeosis; Osler-Webber syndrome; myocardial angiogenesis; plaque neovascularization; telangiectasia; hemophilic joints; angiofibroma; diseases of excessive or abnormal stimulation of endothelial cells, including intestinal adhesions, Crohn's disease, skin diseases such as psoriasis, eczema and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, atherosclerosis, scleroderma, wound granulation and hypertrophic scars, i.e. keloids, and diseases that have angiogenesis as a pathological consequence, such as cat scratch disease and ulcers (Helicobacter pylori), can also be treated with antibodies of the invention. Angiogenic inhibitors can be used to prevent or inhibit adhesions, especially intraperitoneal or pelvic adhesions, such as those resulting after open or laparoscopic surgery, and vaginal contractions. Other conditions that may be beneficially treated using angiogenesis inhibitors include prevention of scarring after transplantation, liver cirrhosis, pulmonary fibrosis after acute respiratory distress syndrome or other pulmonary fibrosis of the newborn, temporary prosthesis implantation, and adhesions after surgery between the brain and the dura. Endometriosis, polyposis, cardiac hypertrophy, as well as obesity, may also be treated by angiogenesis inhibition. These disorders may involve increases in size or growth of other types of normal tissue, such as uterine fibroids, prostatic hypertrophy, and amyloidosis. The compounds and compositions provided herein may be used prophylactically or therapeutically for any of the disorders or diseases described herein.

[00091] In some embodiments, the compounds of the invention, or a pharmaceutically acceptable salt and/or a prodrug thereof, or compositions of the invention are administered to treat cystitis, insulin-dependent diabetes, islet cell transplant rejection; kidney transplant rejection; liver transplant rejection; lung transplant rejection, COPD, or flu.

Cancer Treatment Methods

[00092] More specifically, the present invention also provides a method of treating cancer. A preferred method of treating cancer includes administering a therapeutically effective amount of one or more of the above-mentioned compounds (or salts thereof) to a cancer patient for a time sufficient to treat the cancer.

[00093] For treatment, the compositions provided herein may be administered orally, parenterally (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection or implant), by inhalation spray, via nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or in combination, into suitable unit dosage formulations containing conventional pharmaceutically acceptable carriers, adjuvants and non-toxic vehicles for each route of administration.

[00094] In some embodiments, the selective CXCR2 inhibitors provided herein can be administered in combination with other appropriate therapeutic agents, including, for example, chemotherapeutic agents, radiation, etc. It is understood that such administration may be prior to, subsequent to, or in unison with the second therapeutic agent, such that the therapeutic effects of the second agent are enhanced as compared to administration of the second agent in the absence of the CXCR2 inhibitor. The selection of appropriate agents for use in combination therapy can be made by one skilled in the art in accordance with conventional pharmaceutical principles. The combination of therapeutic agents can act synergistically to effect the treatment or prevention of various disorders, such as, for example, cancer, wounds, renal dysfunction, brain dysfunction or neuronal dysfunction. With this approach, therapeutic efficacy can be achieved with lower dosages of each agent, thereby reducing the potential for adverse side effects.

[00095] In addition to primates, such as humans, a variety of other mammals can be treated according to the method provided herein. For example, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other species of bovine, sheep, equine, canine, feline, rodent or murine may be treated. However, the method can also be practiced on other species, such as birds (e.g. chickens).

[00096] Standard in vivo assays demonstrating that the compositions provided herein are useful for treating cancer include those described in Bertolini, F., et al., Endostatin, an anti-angiogenic drug, induces tumor stabilization after chemotherapy or anti- CD20 therapy in a NOD/SCID mouse model of human high-grade nonHodgkin lymphoma. Blood, No. 1, Vol. 96, pp. 282-87 (July 1, 2000); Pengnian, L., Antiangiogenic gene therapy targeting the endothelium-specific receptor tyrosine kinase Tie2. Proc. Natl. Academic. Sci. USA, Vol. 95, pp. 8829-34 (July 1998); and Pulaski, B. Cooperativity of Staphylococcal aureus Enterotoxin B Superantigen, Major Histocompatibility Complex Class II, and CD80 for Immunotherapy of Advanced Spontaneous Metastases in a Clinically Relevant Postoperative Mouse Breast Cancer Model. Cancer Research, Vol. 60, pp. 2710-15 (May 15, 2000).

[00097] In the treatment or prevention of conditions requiring chemokine receptor modulation, a suitable dosage level will generally be about 0.001 to 100 mg per kg of patient body weight per day, which may be administered in single or multiple doses. Preferably, the dosage level will be about 0.01 to about 25 mg/kg per day; more preferably, about 0.05 to about 10 mg/kg per day. A suitable dosage level may be about 0.01 to 25 mg/kg per day, about 0.05 to 10 mg/kg per day, or about 0.1 to 5 mg/kg per day. Within this dosage range, it can be 0.005 to 0.05, 0.05 to 0.5, or 0.5 to 5.0 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900, 0 and 1000.0 milligrams of the active ingredient for symptomatic dosage adjustment to the patient being treated. The compounds can be administered on a 1 to 4 times per day regimen, preferably once or twice per day.

[00098] It will be understood, however, that the specific dosage level and dosage frequency for any particular patient may vary and will depend on a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, hereditary characteristics, general health, sex and diet of the individual, as well as the mode and time of administration, the rate of excretion, the combination of drugs and the severity of the particular condition of the individual. individual undergoing treatment.

[00099] The compounds and compositions provided herein can be combined with other compounds and compositions having related utilities to prevent and treat cancer and diseases or conditions associated with CXCR2 signaling. Such other drugs may be administered, by a commonly used route and in an amount, concomitantly or sequentially, with a compound or composition provided herein. When a compound or composition provided herein is used simultaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound or composition provided herein is preferable. In this sense, the pharmaceutical compositions provided herein include those that also contain one or more other active ingredients or therapeutic agents in addition to a compound or composition provided herein. Examples of other therapeutic agents that can be combined with a compound or composition provided herein, whether administered separately or in the same pharmaceutical compositions, include, but are not limited to: cisplatin, paclitaxel, methotrexate, cyclophosphamide, ifosfamide, chlorambucil, carmustine, carboplatin, vincristine, vinblastine, thiotepa, lomustine, semustine, 5-fluorouracil and cytarabine. The weight ratio of the proof provided here for the second active ingredient may vary and will depend on the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound provided herein is combined with a second anticancer agent, the weight ratio of the compound provided herein to the second agent will vary between 1000:1 and 1:1000, preferably about 200:1 at about 1:200. Combinations of a compound provided herein and other active ingredients will also be within the aforementioned range, but in each case, an effective dose of each active ingredient must be used. In some embodiments, the compounds of the invention, or a pharmaceutically acceptable salt and/or prodrug thereof, are administered separately or in the same pharmaceutical compositions with: an alkylating agent, a nitrosurea agent, an anticancer antibiotic, an alkaloid of plant origin, a topoisomerase inhibitor, a hormonal drug, a hormonal antagonist, an aromatase inhibitor, a P-glycoprotein inhibitor, a platinum complex derivative, an immunotherapeutic drug or other anticancer drugs, or any combination thereof.

Inflammation Treatment Methods

[000100] Furthermore, the compounds and compositions provided herein are most useful for the treatment of inflammation and can be combined with other compounds and compositions with therapeutic utilities that may require treatment before, after or simultaneously with the treatment of cancer or inflammation with the present compounds. Accordingly, the compositions and methods of combination are also a component of the present invention for preventing and treating conditions or diseases of interest, such as inflammatory or autoimmune disorders, conditions and diseases, including inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, arthritis psoriatic arthritis, polyarticular arthritis, multiple sclerosis, allergic diseases, psoriasis, atopic dermatitis and asthma, and the pathologies mentioned above.

[000101] For example, in the treatment or prevention of inflammation or autoimmunity or, for example, arthritis associated with bone loss, the present compounds and compositions can be used in conjunction with an anti-inflammatory or analgesic agent, such as an opiate agonist, a lipoxygenase inhibitor, such as a 5-lipoxygenase inhibitor, a cyclooxygenase inhibitor, such as a cyclooxygenase 2 inhibitor, an interleukin inhibitor, such as an interleukin 1 inhibitor, an NMDA antagonist, a nitric oxide inhibitor or a nitric oxide synthesis inhibitor, a non-steroidal anti-inflammatory agent, or a cytokine-suppressing anti-inflammatory agent, for example, with a compound such as acetaminophen, aspirin, codeine, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroid analgesic, sufentanil, sunlindac, tenidap and the like. Similarly, the present compounds and compositions can be administered with an analgesic listed above; an enhancer, such as caffeine, an H2 antagonist (e.g., ranitidine), simethicone, aluminum or magnesium hydroxide; a decongestant, such as phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levodeoxy ephedrine; an antitussive, such as codeine, hydrocodone, caramifen, carbetapentane or dextromethorphan; a diuretic; and a sedating or non-sedating antihistamine.

[000102] As noted, the compounds and compositions set forth herein may be used in combination with other drugs that are used in the treatment, prevention, suppression, or amelioration of diseases or conditions for which the compounds and compositions provided herein are useful. Such other drugs may be administered, by a route and in an amount commonly used, concomitantly or sequentially with the compound or composition provided herein. When a compound or composition provided herein is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs, in addition to the compound or composition provided herein, is preferred. In this regard, the pharmaceutical compositions provided herein include those that also contain one or more other active ingredients or therapeutic agents, in addition to a compound or composition provided herein. Examples of other therapeutic agents that may be combined with a compound or composition provided herein, whether administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) VLA-4 antagonists, (b) corticosteroids, such as beclomethasone, methylprednisolone, betamethasone, prednisone, prenisolone, dexamethasone, fluticasone, hydrocortisone, budesonide, triamcinolone, salmeterol, salmeterol, salbutamol, formeterol; (c) immunosuppressants, such as cyclosporine (cyclosporine A, Sandimmune®, Neoral®), tacrolimus (FK-506, Prograf®), rapamycin (sirolimus, Rapamune®) and other FK-506-type immunosuppressants, and mycophenolate, e.g. mycophenolate mofetil (CellCept®); (d) antihistamines (H1-histamine antagonists) such as brompheniramine, chlorpheniramine, dexclopheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methylazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine, fexofenadine, descarboethoxyloratadine, and the like; (e) nonsteroidal antiasthmatics (e.g., terbutaline, metaproterenol, fenoterol, isoetharine, albuterol, bitolterol, and pirbuterol), theophylline, cromolyn sodium, atropine, ipratropium bromide, leukotriene antagonists (e.g., zafmlukast, montelukast, pranlukast, iralukast, pobilukast, and SKB-106,203), leukotriene biosynthesis inhibitors (zileuton, BAY-1005); (f) nonsteroidal anti-inflammatory agents (NSAIDs) such as propionic acid derivatives (e.g., alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen), acetic acid derivatives (e.g., indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidomethacin, and zomepirac), and fenamic acid derivatives (e.g., flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives (e.g. diflunisal and flufenisal), oxicams (e.g. isoxicam, piroxicam, sudoxicam and tenoxicam), salicylates (e.g. acetylsalicylic acid and sulfasalazine) and pyrazolones (e.g. apazone, bezpiperilon, feprazone, mofebutazone, oxyphenbutazone and phenylbutazone); (g) cyclooxygenase-2 (COX-2) inhibitors such as celecoxib (Celebrex®) and rofecoxib (Vioxx®); (h) phosphodiesterase type IV (PDE IV) inhibitors; (i) gold compounds such as auranofin and aurothioglucose, (j) etanercept (Enbrel®), (k) antibody therapies such as orthoclone (OKT3), daclizumab (Zenapax®), basiliximab (Simulect®) and infliximab (Remicade®), (l) other chemokine receptor antagonists, especially CCR5, CXCR2, CXCR3, CCR2, CCR3, CCR4, CCR7, CX3CR1 and CXCR6; (m) lubricants or emollients such as petrolatum and lanolin, (n) keratolytic agents (e.g., tazarotene), (o) vitamin D3 derivatives e.g., calcipotriene or calcipotriol (Dovonex®), (p) PUVA, (q) anthralin (Drithrocreme®), (r) etretinate (Tegison®) and isotretinoin and (s) multiple sclerosis therapeutic agents such as interferon β-1β (Betaseron®), interferon (β-1α (Avonex®), azathioprine (Imurek®, Imuran®), glatiramer acetate (Capoxone®), a glucocorticoid (e.g., prednisolone) and cyclophosphamide (t) DMARDS such as methotrexate, (u) other compounds such as phenytoin 5-aminosalicylic acid and prodrugs thereof; hydroxychloroquine; D-penicillamine; antimetabolites such as azathioprine, 6-mercaptopurine and methotrexate; DNA synthesis inhibitors such as hydroxyurea and microtubule disruptors such as colchicine. The weight ratio of the compounds provided herein to the second active ingredient may vary and will depend on the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound provided herein is combined with an NSAID, the weight ratio of the compound provided herein to the NSAID will generally range from about 1000:1 to about 1:1000, preferably from about 200:1 to about 1:200. Combinations of a compound provided herein and other active ingredients will also generally be within the above range, but in each case an effective dose of each active ingredient should be used.

Method for Diagnosing Diseases and Disorders Associated with CXCR2

[000103] Furthermore, the compounds and compositions of this document are useful for the diagnosis of diseases and disorders associated with CXCR2. In particular, the compounds provided herein can be prepared in a labeled form (e.g., radiolabeled) and used for the diagnosis of cancer, for example. Compounds labeled herein that bind to CXCR2 (e.g., antagonists or agonists) can be used to determine CXCR2 levels in a mammalian subject. In some embodiments, CXCR2 modulators or antagonists are administered to an individual with cancer. In some cases, labeled compounds are administered to detect developing cancers, for example, carcinomas, gliomas, mesotheliomas, melanomas, lymphomas, leukemias, adenocarcinomas, breast cancer, ovarian cancer, cervical cancer, glioblastoma, leukemia, lymphoma, prostate cancer, Burkitt's lymphoma, head and neck cancer, colon cancer, colorectal cancer, non-small cell lung cancer, small cell lung cancer, esophageal cancer, stomach cancer, pancreatic cancer, hepatobiliary cancer, bowel cancer, small bowel cancer, rectal cancer, kidney cancer, bladder cancer, prostate cancer, penile cancer, urethral cancer, testicular cancer, cervical cancer, vaginal cancer, uterine cancer , ovarian cancer, thyroid cancer, parathyroid cancer, adrenal cancer, pancreatic endocrine cancer, carcinoid cancer, bone cancer, skin cancer, retinoblastomas, Hodgkin's lymphoma, non-Hodgkin's lymphoma (see Cancer: Principles and Practice ( DeVita, VT et al. eds 1997). ) for additional cancers); as well as brain and neuronal dysfunction, such as Alzheimer's disease and multiple sclerosis; kidney dysfunction; rheumatoid arthritis; cardiac allograft rejection; atherosclerosis (and high cholesterol levels); asthma; glomerulonephritis; contact dermatitis; inflammatory bowel disease; colitis; psoriasis; reperfusion injury; as well as other disorders and diseases described in this document. In some embodiments, the individual does not have Kaposi's sarcoma, multicentric Castleman's disease, or AIDS-associated primary effusion lymphoma.

[000104] A variety of detection and imaging methods can be used to detect cancers. In some embodiments, direct methods are available to assess the biodistribution of CXCR2 in the body, such as magnetic resonance imaging ("MRI"), positron emission tomography ("PET"), and single photon emission computed tomography. ("SPECT"). Each of these methods can detect the distribution of an appropriately labeled compound (usually linked to CXCR2) within the body if that compound contains an atom with the appropriate nuclear properties. MRI detects paramagnetic nuclei; PET and SPECT detect the emission of particles from the decay of radionuclei.

[000105] For methods involving PET, it is necessary to incorporate an appropriate positron-emitting radionuclide. There are relatively few positron-emitting isotopes that are suitable for labeling a therapeutic agent. The carbon isotope, 11C, has been used for PET but has a short half-life of 20.5 minutes. Thus, facilities for synthesis and use are typically close to a cyclotron, where the 11C precursor starting material is generated. Another useful isotope, 18F, has a half-life of 110 minutes. This allows sufficient time for incorporation into a radiolabeled tracer, for purification, and for administration to a human or animal subject. Other isotopes have even shorter half-lives. 13N has a half-life of 10 minutes and 15O has an even shorter half-life of 2 minutes. The emissions of both are more energetic, however, than those of 11C, and PET studies have been performed with these isotopes (see, Clinical Positron Emission Tomography, Mosby Year Book, 1992, K.F. Hubner, et al., Chapter 2).

[000106] SPECT imaging employs isotopic tracers that are Y-emitters. Although the range of useful isotopes is greater than for PET, SPECT imaging provides lower three-dimensional resolution. However, in some cases, SPECT is used to obtain clinically meaningful information about the binding rates, localization, and clearance of compounds. A useful isotope for SPECT imaging is 123I, an emitter with a half-life of 13.3 hours. 123I-labeled compounds can be shipped up to about 1000 miles from the manufacturing site, or the isotope itself can be transported for on-site synthesis. Eighty-five percent of isotope emissions are 159 KeV photons, which are readily measured by SPECT instrumentation currently in use. Other halogen isotopes can be used for PET or SPECT imaging, or for conventional tracer labeling. These include 75Br, 76Br, 77Br and 82Br having usable half-lives and emission characteristics.

[000107] In view of the above, the present invention provides methods for imaging a tumor, organ or tissue, said method comprising: (a) administering to an individual in need of such imaging, a radiolabeled or detectable form of a compound of Formula I; and (b) detecting said compound to determine where said compound is concentrated in said individual.

[000108] Furthermore, the present invention provides methods for detecting elevated levels of CXCR2 in a sample, said method comprising: (a) contacting a sample suspected of having elevated levels of CXCR2 with a radiolabeled or detectable form of a compound of Formula I; (b) determining a level of compound that is bound to CXCR2 present in said sample to determine the level of CXCR2 present in said sample; and (c) comparing the level determined in step (b) with a control sample to determine whether elevated levels of CXCR2 are present in said sample.

[000109] As with the treatment methods described in this document, administration of the labeled compounds can be done by any of the routes normally used to introduce a compound into final contact with the tissue to be evaluated and is well known to those versed in the technique. Although more than one route may be used to administer a given composition, a particular route may generally provide a more immediate and more effective diagnosis than another route.

Combination Therapies

[000110] CXCR2 inhibitors can be provided alone or in conjunction with one or more other medications. Potential combination partners may include, for example, additional antiangiogenic factors and/or chemotherapeutic agents (e.g., cytotoxic agents) or radiation, a cancer vaccine, an immunomodulatory agent, a checkpoint inhibitor, a antivascular agent, a signal transduction inhibitor, an antiproliferative agent or an inducer of apoptosis.

[000111] Examples of other therapeutic agents that can be combined with a compound or composition of the invention, whether administered separately or in the same pharmaceutical composition, include, but are not limited to: modulators of CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, CX3CR1, ChemR23, C5aR, C5a and C5, or any combination thereof. In some embodiments, the modulator is an antagonist.

[000112] Examples of other therapeutic agents that can be combined with a compound or composition of the present invention, whether administered separately or in the same pharmaceutical compositions, include, but are not limited to: a therapeutic antibody, a bispecific antibody and therapeutic protein "similar and antibody" (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives), an antibody-drug conjugate (ADC), a virus, an oncolytic virus, gene modifiers or editors, such as CRISPR (including CRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs), a monotherapy agent and CAR (chimeric antigen receptor) T cells, cytokines, vaccines, vaccine adjuvants, GM-CSF, M-CSF, G -CSF, interferon-a, beta or gamma, IL-1, IL-2, IL-3, IL-12, Poly (I:C), CPG, cyclophosphamide, cyclophosphamide analogues, anti-TGF and imatinib (Gleevac) , a mitosis inhibitor paclitaxel, Sunitinib (Sutent), antiangiogenic agents, an aromatase inhibitor, letrozole, an adenosine receptor antagonist (A2AR), an adenosine receptor modulator, an A3 adenosine receptor modulator, an inhibitor of angiogenesis, anthracyclines, oxaliplatin, doxorubicin, TLR4 antagonists, IL-18 antagonists, a Btk tyrosine kinase inhibitor, an Erbb2 tyrosine kinase receptor inhibitor; an Erbb4 receptor tyrosine kinase inhibitor, an mTOR inhibitor, a thymidylate synthase inhibitor, an EGFR tyrosine kinase receptor inhibitor, an epidermal growth factor antagonist, a Fyn tyrosine kinase inhibitor, a Kit tyrosine kinase inhibitor , a Lyn tyrosine kinase inhibitor, an NK cell receptor modulator, a PDGF receptor antagonist, a PARP inhibitor, a Poly ADP ribose polymerase inhibitor, a Poly ADP ribose polymerase 1 inhibitor, a Poly ADP ribose polymerase inhibitor 2, a Poly ADP ribose polymerase 3 inhibitor, a galactosyltransferase modulator, a dihydropyrimidine dehydrogenase inhibitor, an orotate phosphoribosyltransferase inhibitor, a telomerase modulator, a Mucin 1 inhibitor, a Mucin inhibitor, an agonist of Secretin, a modulator of TNF-related apoptosis-inducing ligand, an IL17 gene stimulator, an Interleukin 17E ligand, a Neurokinin receptor agonist, a Cyclin G1 inhibitor, a checkpoint inhibitor, a PD inhibitor -1, a PD-L1 inhibitor, a CTLA4 inhibitor, a Topoisomerase I inhibitor, an Alk-5 protein kinase inhibitor, a connective tissue growth factor ligand inhibitor, a Notch-2 receptor antagonist, a Notch-3 receptor antagonist, a Hyaluronidase stimulator, a MEK-1 protein kinase inhibitor, a Phosphoinositide-3 kinase inhibitor, a MEK-2 protein kinase inhibitor, a GM-CSF receptor modulator; a TNF alpha ligand modulator, a Mesothelin modulator, an Asparaginase stimulator, a CSF2 gene stimulator, a Caspase-3 stimulator; a Caspase-9 stimulator, a PKN3 gene inhibitor, a Hedgehog protein inhibitor; softened receptor antagonist, an AKT1 gene inhibitor, a DHFR inhibitor, a thymidine kinase stimulator, a CD29 modulator, a Fibronectin modulator, an Interleukin-2 ligand, a serine protease inhibitor, a D40LG gene stimulator ; a TNFSF9 gene stimulator, an oxoglutarate dehydrogenase 2 inhibitor, a TGF-beta type II receptor antagonist, an Erbb3 tyrosine kinase receptor inhibitor, a cholecystokinin CCK2 receptor antagonist, a tumor protein modulator of Wilms, a Ras GTPase modulator, a Histone deacetylase inhibitor, a Raf B protein kinase inhibitor, a cyclin-dependent kinase 4 inhibitor A modulator, an estrogen receptor beta modulator, a 4-1BB inhibitor, a 4-1BBL inhibitor, a PD-L2 inhibitor, a B7-H3 inhibitor, a B7-H4 inhibitor, a BTLA inhibitor, an HVEM inhibitor, a TIM3 inhibitor, a TI-GIT inhibitor, an NKG2A inhibitor, a GAL9 inhibitor, a LAG3 inhibitor, a PD-1H inhibitor, a PD96 inhibitor, a VISTA inhibitor, a KIR inhibitor, a 2B4 inhibitor, a CD160 inhibitor, a modulator of CD66e, an Angiotensin II receptor antagonist, a connective tissue growth factor ligand inhibitor, a Jak1 tyrosine kinase inhibitor, a Jak2 tyrosine kinase inhibitor, a Jak1/Jak2 dual tyrosine kinase inhibitor, an enzyme stimulator 2, a growth hormone receptor antagonist, a Galectin-3 inhibitor, a checkpoint kinase 2 modulator, a sodium glucose transporter-2 inhibitor, an Endothelin antagonist ET-A, a Mineralocorticoid receptor antagonist, an Endothelin antagonist ET-B, an advanced glycosylation product receptor antagonist, an adrenocorticotropic hormone ligand, a Farnesoid X receptor agonist, a bile acid receptor antagonist coupled to G protein, an Aldose reductase inhibitor, a Xanthine oxidase inhibitor, a PPAR gamma agonist, a Prostanoid receptor antagonist, an FGF receptor antagonist, a PDGF receptor antagonist, a TGF beta antagonist, a modulator of P3 protein, a p38 MAP kinase inhibitor, a VEGF-1 receptor antagonist, a beta protein tyrosine phosphatase inhibitor, a Tek tyrosine kinase receptor stimulator, a PDE 5 inhibitor, a Mineralocorticoid receptor antagonist, a of ACE, an inhibitor of I-kapa B kinase, an NFE2L2 gene stimulator, a nuclear factor kappa B inhibitor, a STAT3 gene inhibitor, an NADPH oxidase 1 inhibitor, a NADPH oxidase 4 inhibitor, a PDE inhibitor 4, a Renin inhibitor, a FURIN gene inhibitor, a MEKK-5 protein kinase inhibitor, a membrane copper amine oxidase inhibitor, an alpha-V/beta-3 Integrin antagonist, an insulin sensitizer, a modulator kallikrein 1, a cyclooxygenase inhibitor, a complement C3 modulator, a Tubulin binding agent, a macrophage mannose receptor 1 modulator, a phenylalanine hydroxylase stimulator, an OX40 agonist, a GITR agonist, a CD40, Denileukin diftitox, Bexarotene, Vorinostat, Romidepsin, Pralatrexate, prednisone, prednisolone, CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX9664, CCX2553, CCX 2991, CCX282, CCX025, CCX430, CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, CCX168-M1, bavituximab, IMM-101, CAP1-6D, Rexin-G, genistein, CVac, MM-D37K, PCI-27483, TG-01, mocetinostat, LOAd-703, CPI- 613, upamostat, CRS-207, NovaCaps, trametinib, Atu-027, sonidegib, GRASPA, trabedersen, nastorazepid, Vaccell, oregovomab, istiratumab, refametinib, regorafenib, lapatinib, selumetinib, rucaparib, pelareorep, tarextumab, PEGylated hyaluronidase, varlitinib , aglatimagen besadenovec, GBS-01, GI-4000, WF-10, galunisertib, afatinib, RX-0201, FG-3019, per-tuzumab, DCVax-Direct, selinexor, glufosfamide, virulizin, clivatuzumab yttrium tetraxetane (90Y ), brivudine, nimotuzumab, algenpantucel-L, tegafur + gimeracil + oteracil potassium + calcium folinate, olaparib, ibrutinib, pirarubicin, Rh-Apo2L, tertomotide, tegafur + gimeracil + oteracil potassium, tegafur + gimeracil + oteracil potassium, masitinib , Rexin-G, mitomycin, erlotinib, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, platinum derivatives, taxane, paclitaxel, vinca alkaloids, vinblastine, anthracyclines, doxorubicin, epipodophyllotoxins, etoposide , cisplatin, rapamycin, methotrexate, actinomycin D, dolastatin 10, colchicine, emetine, trimetrexate, metoprine, cyclosporine, daunorubicin, teniposide, amphotericin, alkylating agents, chlorambucil, 5-fluorouracil, camptothecin, cisplatin, metronidazole, Gleevec , Avastin, Vectibix, abarelix, aldes-leukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, anastrozole, arsenic trioxide, asparaginase, azacitidine, AZD9291, BCG Live, bevacuzimab, fluorouracil, bexarotene, bleomycin, borte-zomib, busulfan, calusterone , capecitabine, camptothecin, carboplatin, carmustine, celecoxib, cetuximab, chlorambucil, cladribine, clofarabine, cyclophosphamide, cytarabine, dactinomycin, darbepoetin alfa, daunorubicin, denileukin, dexrazoxane, docetaxel, doxorubicin (neutral), doxorubicin hydrochloride, propionate dromostanolone, epirubicin, epoetin alfa, estramustine, etoposide phosphate, etoposide, exemestane, filgrastim, floxuridine fludarabine, fulvestrant, gefitinib, gemcitabine, gemtuzumab, goserelin acetate, histrelin acetate, hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib mesylate, interferon alfa-2a, interferon alfa-2b, irinotecan, lenalidomide, letrozole, leucovorin, leuprolide acetate, levadamisole, lomustine, megestrol acetate, melphalan, mercaptopurine, 6-MP, mesna, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone, Nelarabine, nofetumomab, oprelvecin, oxaliplatin, nab-paclitaxel, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, porfimer sodium, procarbazine , quinacrine, rasburicase, rituximab, rociletinib, sargramostima, sorafenib, streptozocin, sunitinib maleate, talc, tamoxifen, temozolomide, teniposide, VM-26, testolactone, thioguanine, 6-TG, thiotepa, topotecan, toremifene, tositumomab, trastuzumab , tretinoin, ATRA, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, zoledronate, zoledronic acid, pembrolizumab, nivolumab, IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF- 06801591, PDR-001, GB-226, STI-1110, durvalumab, atezolizumab, avelumab, BMS-936559, ALN-PDL, TSR-042, KD-033, CA-170, STI- 1014, FOLFIRINOX, KY- 1003, olmesartan medoxomil, candesartan, PBI-4050, baricitinib, GSK-2586881, losartan, dapagliflozin, propanediol, pegvisomant, GR-MD-02, canagliflozin, irbesartan, FG-3019, atrasentan, finerenone, sparsentan, bosentan, defibrotide, fimasartan, azeliragon, pyridoxamine, corticotropin, INT-767, epalrestat, topiroxostat, SER-150-DN, pirfenidone, VEGFR-1 mAb, AKB-9778, PF- 489791, SHP-627, CS-3150, imidapril, perindopril , captopril, enalapril, lisinopril, Zofenopril, Lisinopril, Quinapril, Benazepril, Trandolapril, Cilazapril, Fosinopril, Ramipril, bardoxolone methyl, irbesartan + propager-manium, GKT-831, MT-3995, TAK-648, TAK-272, GS-4997, DW-1029M, ASP-8232, VPI-2690B, DM-199, rhein, PHN-033, GLY-230, and sapropterin, sulodexide, lirilumab, IPH-4102, IPH-2101, IMP-321 , BMS-986016, MGD-013, LAG-525, durvalumab, monalizumab, MCLA-134, MBG-453, CA-170, AUPM-170, AUPM-327, resminostat, ipilimumab, BGB-A317, tremelimumab, REGN-2810 , AZD-5069, masitinib, binimetinib, trametinib, ruxolitinib, dabrafenib, linaclotide, ipilimumab, apatinib, nintedanib, cabozantinib, Pazopanib, belinostat, panitumumab, guadecitabine, vismodegib, vemurafenib, dasatinib, tremelimumab, bevacizumab, oxaliplatin , aflibercept, vandetanib, everolimus, thalidomide, veliparib, encorafenib, napabucasin, alpelisib, axitinib, cediranib, necitumumab, ramucirumab, irofulven, trifluridine + tipiracil, donafenib, pacritinib, pexastimogen devacirepvec, tivantinib, GNR-011, talaporfin, piclidenosone, decitabine, ganitumab, panobinostat, rintatolimod, polmacoxib, levofolinate, famitinib, votumumab, tivozanib, entinostat, plitidepsin, lefitolimod, OSE-2101, vitespene, TroVax, bromocriptine, midostaurin, fosbretabulin, fruquintinib, ganetespib, brivanib, anloti- , L19-TNF-alpha, racotumomab, Novaferon, raltitrexed, enzastaurin, GM-CT-01, arcitumomab, or any combination of these.

Kits and Packaging

[000113] The terms "kit" and "pharmaceutical kit" refer to a kit or commercial packaging containing, in one or more suitable containers, one or more pharmaceutical compositions and instructions for their use. In one embodiment, kits containing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and instructions for administration thereof are provided. In one embodiment, kits with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents and instructions for its administration are provided.

[000114] In one embodiment, the compounds of this invention are formulated in administration units that are packaged in a single package. Individual packaging includes, but is not limited to, a bottle, a child-resistant bottle, an ampoule and a tube. In one embodiment, the compounds of this invention and optional additional therapeutic agents are formulated into administration units and each administration unit is individually packaged in a single package. Such individually packaged units may contain the pharmaceutical composition in any form including, but not limited to, liquid form, solid form, powder form, granule form, an effervescent powder or tablet, hard or soft capsules, emulsions, suspensions, syrup, suppositories , tablets, troches, lozenges, solution, mouth patch, thin film, oral gel, chewable tablet, chewing gum and single-use syringes. These individually packaged units can be combined into a package made of paper, cardboard, cardboard, metal foil and plastic foil, for example a blister. One or more administration units may be administered once or several times a day. One or more administration units may be administered three times per day. One or more administration units may be administered twice daily. One or more administration units may be administered on a first day and one or more administration units may be administered on subsequent days.

General Synthetic Procedure

[000115] Embodiments are also directed to processes and intermediates useful for preparing the compounds in question or their pharmaceutically acceptable salts.

[000116] Exemplary chemical entities useful in the methods of the embodiments will now be described by reference to illustrative synthetic schemes for their general preparation in this document and the specific examples that follow. Those skilled in the art will recognize that, to obtain the various compounds of this document, the starting materials can be suitably selected so that the desired substituents are transported through the reaction scheme with or without protection as appropriate to produce the desired product. Alternatively, it may be necessary or desirable to employ, in place of the desired substituent, a suitable group that can be transported through the reaction scheme and replaced as appropriate by the desired substituent. Furthermore, one skilled in the art will recognize that the transformations shown in the schemes below can be performed in any order that is compatible with the functionality of the particular pendant groups.

[000117] Representative syntheses of compounds of the present invention are described in the schemes below and in the particular examples that follow. Schemes 1 and 2 are provided as a further embodiment of the invention and illustrate the general methods that have been used to prepare the compounds of the present invention, including the compounds of Formula (I), (Ia) and (Ib) and which can be used to prepare additional compounds having Formula (I), (Ia) and (Ib). The methodology is compatible with a wide variety of functionalities. Scheme 1

[000118] The amino group of A1 can be reacted with 3,4-dimethoxycyclobut-3-ene-1,2-dione to provide A2. A2 can then be reacted with the amino group of A3 to provide A4. Scheme 2

[000119] A7 can be obtained by reducing the cyano group in A6, for example, by hydrogenation, followed by cyclization. Alternatively, A5 (where X represents a leaving group such as a halogen or a tosylate and where R is an alkyl group) can be reacted with NH3 to form the cyclized product A7. A7 can be obtained with HNO3 to introduce the nitro group in the presence of an acid such as sulfuric acid to give A8. Subsequent reduction of the nitro group in A8, for example, by hydrogenation can provide A9.

EXAMPLES

[000120] The following examples are provided to illustrate, but not to limit the claimed invention.

[000121] The reagents and solvents used below can be obtained from commercial sources, such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). 1H-NMR spectra were recorded on a 400 MHz Varian Mercury NMR spectrometer. Significant peaks are provided in relation to TMS and are tabulated in the order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet) and number of protons. Mass spectrometry results are reported as the ratio of mass to charge, followed by the relative abundance of each ion (in parentheses). In the examples, a single value of m/e is reported for the ion M+H (or, as noted, M-H) containing the most common atomic isotopes. Isotope patterns match the expected formula in all cases. Electrospray ionization (ESI) mass spectrometry analysis was conducted on a Hewlett-Packard MSD electrospray mass spectrometer using the HP1100 HPLC for sample delivery. Typically, the analyte was dissolved in methanol at 0.1 mg/mL and 1 microliter was infused with the delivery solvent into the mass spectrometer, which scanned at 100 to 1500 daltons. All compounds could be analyzed in positive ESI mode, using acetonitrile/water with 1% formic acid as the delivery solvent. The compounds provided below could also be analyzed in negative ESI mode, using 2 mM NH4OAc in acetonitrile/water as the delivery system.

[000122] The following abbreviations are used in the examples and throughout the description of the invention: rt, room temperature; HPLC, high pressure liquid chromatography; TFA, trifluoroacetic acid; LC-MSD, mass selective detector/liquid chromatography; LC-MS, mass spectrometer/liquid chromatography; Pd2dba3, tris(dibenzylidene-acetone)dipalladium; THF, tetrahydrofuran; DMF, dimethylformamide or N,N-dimethylformamide; DCM, dichloromethane; DMSO, dimethyl sulfoxide; TLC, thin layer chromatography; KHMDS, potassium hexamethyldisilazane; ES, electrospray; sat., saturated.

[000123] Compounds within the scope of the present invention can be synthesized as described below, using a variety of reactions known to those skilled in the art. One skilled in the art will also recognize that alternative methods may be employed to synthesize the target compounds of the present invention, and that the approaches described within the body of this document are not exhaustive, but effectively provide broadly applicable and practical routes to compounds of interest.

[000124] Certain molecules claimed in this patent can exist in different enantiomeric and diastereomeric forms and all variants of these compounds are claimed.

[000125] The detailed description of the experimental procedures used to synthesize key compounds in this text leads to molecules that are described by the physical data that identify them, as well as the structural representations associated with them.

[000126] Those skilled in the art will also recognize that during standard working procedures in organic chemistry, acids and bases are frequently used. Salts of the parent compounds are sometimes produced, if they have the requisite intrinsic acidity or basicity, during the experimental procedures described in this patent. Example 1: Synthesis of 3-[(5-fluoro-3-oxo-isoindolin-4-yl)amino]-4-[[(1R)-1-(5-methyl-2-furyl)propyl]amino]cyclobut-3-ene-1,2-dione

[000127] Step a: A 500 ml round bottom flask was charged with methyl 2-bromo-5-fluorobenzoate (48 g, 206 mmol), copper cyanide (37 g, 412 mmol) and DMF (200 ml ). The mixture was heated to 110°C overnight and then cooled to room temperature. Ether (1.5 L) and Celite (100 g) were added and the mixture was stirred at room temperature for 30 minutes. The solid was filtered and the filtrate was washed with brine (3 x 200 ml) and then dried over MgSO4. The solvent was evaporated under reduced pressure to give the desired product as a colorless solid (31 g, 84%). MS: (ES) m/z calculated for C9H7FNO2[M + H]+ 180, found 180.

[000128] Step b: To a solution of methyl 2-cyano-5-fluorobenzoate (10 g, 56 mmol) in methanol (200 ml), 10% Pd-C (1.0 g) was added at room temperature. The resulting mixture was stirred under a hydrogen atmosphere (50 psi) overnight. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to give the desired product as a colorless solid (8.0 g, 90%). MS: (ES) m/z calculated for C8H7FNO[M + H]+ 152, found 152.

[000129] Step c: To a suspension at 0°C of 6-fluoroisoindoline-1-one (8.0 g, 5.3 mmol) in concentrated H2SO4, a pre-cooled mixture of concentrated H2SO4 (26 ml) and nitric acid (6 ml) while keeping the reaction mixture below 5°C. After addition, the reaction mixture was slowly warmed to room temperature overnight. Ice (50 g) was added to the mixture and the solid was collected and dried, then washed with MTBE (50 ml) and ethyl acetate (50 ml) to give the desired product as a light yellow solid (5.1 g , 50%). MS: (ES) m/z calculated for C8H6FN2O3[M + H]+ 197, found 197.

[000130] Step d: A solution of 6-fluoro-7-nitroisoindoline-1-one (11.3 g, 57 mmol) and 10% Pd/C (50% moisture, 6.2 g, 2.9 mmoles, 0.05 equiv) in THF (300 ml) was stirred under a hydrogen atmosphere (balloon) overnight. The solid was filtered through Celite and the filtrate was concentrated under reduced pressure to give a colorless solid, which was purified by silica gel chromatography (100% ethyl acetate) to give the desired product as a white solid (6. 4g, 67%). MS: (ES) m/z calculated for C8H9FN2O[M + H]+ 168, found 168.

[000131] Step e: A mixture of 7-amino-6-difluoro-isoindolin-1-one (4.4 g, 26 mmol) and 3,4-dimethoxycyclobut-3-ene-1,2-dione (7, 4 g, 52 mmol) in anhydrous methanol (30 ml) was stirred at 60°C overnight and then at 80°C for 5 h. The reaction mixture was evaporated and the residue was stirred in ethyl acetate (200 ml) at 50°C for 30 min, then cooled to room temperature. The mixture was filtered and dried to give a light yellow solid (5.0 g, 70%). MS: (ES) m/z calculated for C13H10FN2O4 [M + H]+ 277, found 277.

[000132] Step f: A 20 ml vial was charged with 3-[(5-fluoro-3-oxo-isoindolin-4-yl)amino]-4-methoxy-cyclobut-3-ene-1,2-dione (29.8 mg, 0.108 mmol), followed by (1R)-1-(5-methyl-2-furyl)propan-1-amine (25.2 mg, 0.181 mmol) in ethanol (1 ml). The reaction mixture was stirred at room temperature overnight. After gently blowing nitrogen over the reaction mixture to remove most of the solvent, dichloromethane and 1N-hydrochloric acid were added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted twice more with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the crude material was purified using silica gel column chromatography using a mixture of dichloromethane and ethyl acetate as the eluent. 3-[(5-Fluoro-3-oxo-isoindolin-4-yl)amino]-4-[[(1R)-1-(5-methyl-2-furyl)propyl]amino]cyclobut-3-ene- 1,2-dione (27.8 mg, 0.0725 mmol) was obtained in 67% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.72 (s, 1H), 8.26 (d, J = 9.1 Hz, 1H), 7.47 (dd , J = 11.2, 8.3 Hz, 1H), 7.34 (dd, J = 8.3, 3.8 Hz, 1H), 6.26 (d, J = 3.1 Hz, 1H) , 6.05 (dd, J = 3.0, 1.3 Hz, 1H), 5.08 (dd, J = 8.1, 8.1 Hz, 1H), 4.33 (s, 2H), 2.26 (s, 3H), 1.91 (ddq, J = 28, 8.1, 7.3 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H). MS: (ES) m/z calculated for C20H18FN3O4 [M + H]+ 384.1, found 384.3. Example 2: Synthesis of 3-[(5-fluoro-3-oxo-isoindolin-4-yl)amino]-4-[[(1R)-2-methyl-1-(5-methyl-2-furyl)propyl ]amino]cyclobut-3-ene-1,2-dione

[000133] Step a: To a 500 ml round bottom flask, (S)-2-methylpropane-2-sulfinamide (12.1 g, 100 mmoles) was added followed by dichloromethane (100 ml) at room temperature. 5-Methylfuran-2-carboxaldehyde (10.9 ml, 110 mmol) in dichloromethane (13 ml) and titanium ethoxide (51 ml, 219 mmol) in dichloromethane (87 ml) were added. The reaction mixture was stirred overnight. The reaction was diluted with dichloromethane (150 ml) and quenched with sodium sulfate decahydrate (51 g). The reaction mixture was filtered through celite and rinsed with dichloromethane. Evaporation of the solvent gave crude (S)-2-methyl-N-[(5-methyl-2-furyl)methylene]propane-2-sulfinamide (20.89 g, 97.9 mmol) which was used directly in the following reaction .

[000134] Step b: (S)-2-methyl-N-[(5-methyl-2-furyl)methylene]propane-2-sulfinamide (1.76 g, 8.19 mmol) was dissolved in toluene (40 ml) and the reaction was cooled to -70°C using an isopropyl alcohol/dry ice bath. Magnesium isopropyl chloride (8.2 ml, 2M solution in THF, 16.4 mmol) was added over 10 minutes. The reaction was gradually warmed to room temperature and stirred overnight. The reaction was quenched by the addition of saturated aqueous ammonium chloride. Organic materials were extracted using diethyl ether three times followed by a brine wash. The organic layer was dried over anhydrous sodium sulfate and, after removing the solvent under reduced pressure, the crude mixture was purified using a silica gel column using methyl tert-butyl ether/dichloromethane as eluent. (S)-2-Methyl-N-[(1R)-2-methyl-1-(5-methyl-2-furyl)propyl]propane-2-sulfinamide was obtained after removal of solvent under reduced pressure (530 mg 2.06 mmoles, 90% from NMR).

[000135] Step c: Acetyl chloride (0.366 ml, 5.15 mmol) was added dropwise to methanol (5 ml) at 0°C to prepare a solution of anhydrous hydrogen chloride in methanol. This solution was added to (S)-2-methyl-N-[(1R)-2-methyl-1-(5-methyl-2-furyl)propyl]propane-2-sulfinamide (530 mg, 2. 06 mmoles) at 0°C. The reaction was slowly warmed to room temperature for 2 hours. Saturated sodium bicarbonate solution was added to neutralize the reaction mixture and the product was extracted with dichloromethane four times. The combined organic layer was dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure yielded the crude material (310 mg, 2.03 mmoles) which was used directly in the next reaction.

[000136] Step d: A 3-[(5-fluoro-3-oxo-isoindolin-4-yl)amino]-4-methoxy-cyclobut-3-ene-1,2-dione (42.3 mg, 0.146 mmol), (1R)-2-methyl-1-(5-methyl-2-furyl)propan-1-amine (30.5 mg, 0.199 mmol) in ethanol (1 ml) was added at room temperature. The reaction mixture was stirred overnight at 45°C followed by stirring at 65°C for 5 hours. A stream of nitrogen was gently blown over the reaction mixture to remove most of the solvent. Dichloromethane and 1N-hydrochloric acid were added and the layers were separated. The aqueous layer was extracted twice more with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the crude material was purified by silica gel column chromatography using a mixture of dichloromethane and ethyl acetate as the eluent. 3-[(5-Fluoro-3- oxo-isoindolin-4-yl)amino]-4-[[(1R)-2-methyl-1-(5-methyl-2-furyl)propyl]amino] cyclobut- 3-ene-1,2-dione (52.4 mg, 0.132 mmol) was obtained in 90% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.71 (s, 1H), 8.31 (d, J = 9.7 Hz, 1H), 7.48 (dd , J = 11.1, 8.3 Hz, 1H), 7.34 (dd, J = 8.3, 3.8 Hz, 1H), 6.22 (d, J = 3.1 Hz, 1H) , 6.05 (d, J = 3.0 Hz, 1H), 4.97 (t, J = 8.5 Hz, 1H), 4.33 (s, 2H), 2.27 (s, 3H) , 2.18 (dt, J = 13.7, 6.8 Hz, 1H), 0.96 (d, J = 6.7 Hz, 3H), 0.88 (d, J = 6.7 Hz, 3H). MS: (ES) m/z calculated for C21H20FN3O4 [M + H]+ 398.2, found 398.4. Example 3: Synthesis of 3-[(5,7-difluoro-3-oxo-isoindolin-4-yl)amino]-4- [[(1R )-1-(5-methyl-2-furyl)propyl]amino ]cyclobut-3-ene-1,2-dione

[000137] Step a: 3,5-Difluoro-2-methyl-benzoic acid (5.2 g, 30.2 mmol) was dissolved in anhydrous DMF (30 mL). Anhydrous Na2CO3 (3.5 g, 33.2 mmol, 1.1 equiv) was added and the reaction was stirred at room temperature for 30 min. Methyl iodide (2.1 mL, 33.2 mmol, 1.1 equiv) was added and the mixture was stirred at room temperature for 4 h, then the reaction was diluted with water (200 mL) and the product was extracted using Et2O (3 x 50 mL). The combined organic layers were washed with brine (4 x 30 mL), dried over MgSO4, filtered, and evaporated to give a yellow oil (5.4 g, 96%).

[000138] Step b: The product from Step a (5.4 g, 29.0 mmol) was dissolved in carbon tetrachloride (60 ml) and N-bromosuccinimide (7.7 g, 43.5 mmol, 1 .5 equiv) was added followed by benzoyl peroxide (1.4 g, 5.8 mmol, 0.20 equiv). The reaction mixture was stirred at reflux overnight, then cooled to room temperature and filtered. The filtrate was evaporated and the residue was purified by column chromatography (silica gel, 100% hexanes to 9:1 hexanes:ethyl acetate) to give the product as a yellow oil (7.4 g, 96%).

[000139] Step c: NH3 in methanol (7 M, 45 ml, 6.4 mmol) was cooled to 0°C and the product from Step b (6 g, 22.6 mmol) was added. The reaction mixture was stirred at 0°C for 10 minutes and then at room temperature overnight. Excess solvent was evaporated and the residue was diluted with water (50 ml). The resulting solid was filtered and washed with water (2 x 20 ml) then hexanes (20 ml) to give the product (3.4 g, 89%). MS: (ES) m/z calculated for C8H6F2NO [M + H]+170.04, found 170.3.

[000140] Step d: The 4,6-difluoroisoindolin-1-one from Step c (3.4 g, 20.1 mmol) was dissolved in concentrated H2SO4 (40 ml) and cooled to 0°C. 70% HNO3 (1.5 ml, 24.1 mmol, 1.2 equiv) was added dropwise and the reaction mixture was stirred at 0°C for 10 minutes, then allowed to warm to room temperature for a period of time. 1 hour and stirred overnight. Ice was added and the mixture was then diluted with cold water (100 ml). The resulting yellow solid was filtered, washed with water (2 x 50 ml), then hexanes (50 ml) and dried under vacuum (3.4 g, 79%). MS: (ES) m/z calculated for C8H5F2N2O3 [M + H]+215.03, found 215.2.

[000141] Step e: The 4,6-difluoro-7-nitro-isoindolin-1-one from Step d (3.4 g, 15.9 mmoles) was diluted with THF (50 ml) and Pd/C at 10 %, 50% moisture, (1.7 g, 0.8 mmol, 5% mmol) was added under a nitrogen atmosphere. The reaction mixture was vigorously stirred under H2 (flask) for 1 day at room temperature, then filtered through Celite and evaporated to give the solid product (2.7 g, 92%). MS: (ES) m/z calculated for C8H7F2N2O [M + H]+ 185.05, found 185.3.

[000142] Step f: A mixture of 7-amino-4,6-difluoro-isoindolin-1-one from Step e (2.3 g, 12.5 mmol) and 3,4-dimethoxycyclobut-3-ene-1 ,2-dione (3.5 g, 25.0 mmol, 2.0 equiv) in anhydrous MeOH (15 ml) was stirred at 60°C overnight. The reaction mixture was evaporated and the residue was diluted with MTBE:EtOAc (1:1, 200 ml) and stirred at 50°C for 30 min, then cooled to room temperature. The solid product was filtered, washed with MTBE, then dissolved in MeOH:DCM (1:1, 200 ml) and filtered through Celite. The filtrate was evaporated to give a gray solid (2.0 g, 54%). MS: (ES) m/z calculated for C13H9F2N2O4 [M + H]+ 295.05, found 295.3.

[000143] Step g: A 20 mL vial was charged with 3-[(5,7-difluoro-3-oxo-isoindolin-4-yl)amino]-4-methoxy-cyclobut-3-ene-1,2-dione (44.3 mg, 0.144 mmol), followed by (1R)-1-(5-methyl-2-furyl)propan-1-amine (25 mg, 0.18 mmol) in ethanol (1 mL). The reaction mixture was stirred at room temperature overnight, then at 80 °C for 2 h. After gently blowing nitrogen over the reaction mixture to remove most of the solvent, dichloromethane and 1N-hydrochloric acid were added to the reaction mixture. The organic layer was separated, and the aqueous layer was extracted twice more with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the crude material was purified by silica gel column chromatography using a mixture of dichloromethane and ethyl acetate as the eluent. The obtained product was resuspended in ethyl acetate and filtered. The solid was filtered and dried under vacuum to give 3-[(5,7-Difluoro-3-oxo-isoindolin-4-yl)amino]-4-[[(1R)-1-(5-methyl-2-furyl)propyl]amino]cyclobut-3-ene-1,2-dione (22.6 mg, 0.0563 mmol) in 39% yield. 1H NMR (400 MHz, DMSO-d) = 3.0 Hz, 1H), 5.07 (dd, J = 7.6, 7.6 Hz, 1H), 4.41 (s, 2H), 2.26 (s, 3H), 1.90 (ddq, J = 27, 7.6, 7.3 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H). MS: (ES) m/z calculated for C20H17F2N3O4 [M + H]+ 402.1, found 402.4. Example 4: Synthesis of 3-(((S)-5-fluoro-1-methyl-3-oxoisoindolin-4-yl)amino)-4-((( R )-1-(5-methylfuran-2-yl)propylyl)amino)cyclobut-3-ene-1,2-dione and 3-((( R )-5-fluoro-1-methyl-3-oxoisoindolin-4-yl)amino)-4-((( R )- 1-(5-methylfuran-2-yl)propylyl)amino)cyclobut-3-ene-1,2-dione

[000144] Step a: To a stirred solution of 6-fluoroisoindolin-1-one (10 g, 66.2 mmol) in anhydrous dichloromethane (100 ml), triethylamine (16.72, 165.5 mmol, 21. 8 ml), (Boc)2O (17.3 g, 79.4 mmol) and catalytic DMAP (100 mg) at room temperature. The reaction mixture was stirred at room temperature for 16 h. Upon completion, the reaction mixture was diluted with CH2Cl2, washed with H2O and then saturated aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude compound was purified by silica gel chromatography (0-30% ethyl acetate in hexanes) to give the product. MS: (ES) m/z calculated for C13H14FNO3 [M + H]+252.3, found 252.3.

[000145] Step b: 1) To a stirred solution of tert-butyl-6-fluoro-1-oxoisoindoline-2-carboxylate (5.0 g, 19.9 mmol) in anhydrous THF (40 ml) at -78 oC under N2 atmosphere, LiHMDS (21.89 ml, 21.89 mmol) was added dropwise. After the solution was stirred for 30 min, a solution of methyl iodide (2.82 g, 19.92 mmol) in THF (5 ml) was added to the mixture. The reaction mixture was stirred at -78oC for 1 h and then the mixture was allowed to warm to room temperature and stirred for 2 h. Upon completion, the reaction mixture was quenched with saturated aqueous NH4Cl, diluted with EtOAc (100 ml), and the organic layer was washed with H2O and then brine solution. The organic layer was then dried over Na2SO4, filtered and concentrated in vacuo. The crude product was used directly in the next step without any further purification. 2) To a stirred solution of tert-butyl-5-fluoro-1-methyl-3-oxoisoindoline-2-carboxylate (6.2 g, 66.2 mmol) in MeOH (60 ml), 4N HCl in dioxane was added (79.6 mmoles, 20 ml). The mixture was stirred at room temperature for 3 h. After completion of the reaction, the solvent was removed and the reaction mixture was diluted with EtOAc (3x50 ml), the organic layer was washed with H2O and then saturated aqueous NaHCO3. The organic layer was then dried over Na2SO4, filtered and concentrated. The crude compound was purified by silica gel chromatography (10-80% ethyl acetate in hexanes) to give the product. MS: (ES) m/z calculated for C9H8FNO [M + H]+ 166.2, found 166.2.

[000146] Step c: 1) To a stirred solution of 6-fluoro-3-methyliso-indolin-1-one (2.5 g, 15.1 mmol) in anhydrous THF (25 ml) at -78oC under an atmosphere of N2, n-BuLi (6.64 ml, 16.61 mmol, 2.5 M in hexane) was added dropwise and the reaction mixture was stirred at -78°C for 30 min, a solution of (1R,2S ,5R)-2-isopropyl-5-methylcyclohexyl chloroformate (3.96 g, 18.18 mmol) in THF (5 ml) was added to the mixture. The reaction mixture was stirred at −78°C for 30 min, then the reaction mixture was allowed to warm to room temperature and stirred for 3 h. After completion of the reaction, the reaction mixture was quenched with saturated NH4Cl solution, extracted with EtOAc (2x75 ml), the combined organic layer was washed with H2O and brine solution, dried over Na2SO4, filtered and concentrated in vacuo. The crude compound was purified by silica gel chromatography to give (1S)-(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 5-fluoro-1-methyl-3-oxoisoindoline-2-carboxylate and ( 1R)-(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 5-fluoro-1-methyl-3-oxoisoindoline-2-carboxylate separately. 2) To a stirred solution of a diastereomer obtained above (1.2 g, 3.45 mmol) in MeOH (10 ml), Mg(OMe)2 (1012% wt) in MeOH (17.2 mmol, 10 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the solvent was removed and the reaction mixture was quenched with saturated NH4Cl solution, extracted with EtOAc (2x75 ml), the combined organic layer was washed with H2O and brine solution, dried over Na2SO4, filtered and concentrated in vacuo. The crude compound was purified by silica gel, chromatography (2060%), ethyl acetate/hexane to give the desired product. MS: (ES) m/z calculated for C9H8FNO [M + H]+ 166.2, found 166.2. The other diastereomer was treated in a similar way to give the other desired product.

[000147] Step d: 1) One of the compounds obtained from Step c (0.45 g, 2.72 mmol) was dissolved in concentrated H2SO4 (5 ml) and cooled to 0°C. 70% HNO3 (0.34 g, 24.1 mmol, 2.0 equiv) was added dropwise and the reaction mixture was stirred at 0°C for 10 minutes, then allowed to warm to room temperature and stirred for at night. Ice was added and the mixture was then diluted with cold water (10 ml), the reaction mixture was extracted with EtOAc (2x25 ml), washed with H2O and brine solution, dried over Na2SO4, filtered and concentrated. The crude product was used directly in the next step without any further purification. MS: (ES) m/z calculated for C9H7F2N2O3 [M+H]+ 211.0, found 211.2. The other enantiomer was treated in a similar way to give the other desired product. 2) One of the compounds obtained above (0.35 g, 1.32 mmol) and 10% Pd/C (50% moisture, 100 mg) in MeOH (25 ml) was stirred under a hydrogen atmosphere (pair agitator). ) for 1 h at 40 psi. The mixture was filtered through Celite and washed with MeOH (40 ml), the filtrate was concentrated under reduced pressure to give a colorless solid, which was purified by silica gel chromatography (20-100% ethyl acetate/hexanes) to give the desired product. MS: (ES) m/z calculated for C9H9FN2O[M+H]+ 181.1, found 181.2. The other enantiomer was treated in a similar way to give the other desired product.

[000148] Step e: A mixture of one of the compounds obtained in Step d (170 mg, 0.939 mmol) and 3,4-dimethoxycyclobut-3-ene-1,2-dione (200 mg, 1.40 mmol) in methanol anhydrous (4 ml) was stirred at 60°C for 3 h. The reaction mixture was evaporated and the residue was stirred in ethyl acetate (10 ml) at 50°C for 30 min, then cooled to room temperature. The mixture was filtered and dried to give the desired product. MS: (ES) m/z calculated for C14H11FN2O4 [M+H]+ 291.1, found 291.2. The other enantiomer was treated in a similar way to give the other desired product.

[000149] Step f: A 20 ml vial was charged with one of the compounds obtained above (29.0 mg, 0.100 mmol), followed by (1R)-1-(5-methyl-2-furyl) tartrate salt propan-1-amine (28.9 mg, 0.100 mmol) in methanol (0.5 ml) and triethylamine (40.5 mg, 0.400 mmol). The reaction mixture was stirred at 60°C for 3 hours. After gently blowing nitrogen over the reaction mixture to remove the solvent, the crude material was purified using reversed-phase HPLC using a mixture of water and acetonitrile as the eluent to give the desired product. 1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.80 (s, 1H), 8.27 (d, J = 9.0 Hz, 1H), 7.48 (dd , J = 11.1, 8.3 Hz, 1H), 7.37 (dd, J = 8.2, 3.8 Hz, 1H), 6.27 (d, J = 3.1 Hz, 1H) , 6.06 (m, 1H), 5.08 (m, 1H), 4.59 (q, J = 6.6 Hz, 1H), 2.27 (s, 3H), 1.92 (m, 2H), 1.36 (d, J = 6.6 Hz, 3H), 0.92 (t, J = 7.3 Hz, 3H). MS: (ES) m/z calculated for C21H20FN3O4 [M + Na]+ 420.1, found 420.4. The other diastereomer was obtained in a similar way. 1H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.80 (s, 1H), 8.29 (d, J = 8.1 Hz, 1H), 7.48 (dd , J = 11.1, 8.2 Hz, 1H), 7.37 (dd, J = 8.3, 3.8 Hz, 1H), 6.27 (d, J = 3.1 Hz, 1H) , 6.09 - 6.04 (m, 1H), 5.13 - 5.05 (m, 1H), 4.65 - 4.54 (m, 1H), 2.27 (s, 3H), 1 .92 (m, 2H), 1.36 (d, J = 6.7 Hz, 3H), 0.92 (t, J = 7.3 Hz, 3H). MS: (ES) m/z calculated for C21H20FN3O4 [M + Na]+420.1, found 420.3. Example 5: Synthesis of (R)-3-((5-fluoro-1,1-dimethyl-3-oxoisoindolin-4-yl)amino)-4-((1-(5-methylfuran-2-yl)propylyl )amino)cyclobut-3-ene-1,2-dione

[000150] Step a: A mixture of methyl 2-bromo-5-fluorobenzoate (5.00 g, 21.5 mmol) and copper cyanide (2.12 g, 23.6 mmol) in DMF was heated at 90 °C for 1 day, then cooled to room temperature, diluted with ethyl acetate (300 mL), and filtered. The filtrate was washed with brine (5 × 50 mL) and then with saturated NaHCO 3 (50 mL). The organic layer was dried over MgSO 4, filtered, concentrated in vacuo . This product was used in the next step without further purification. MS: (ES) m/z calculated for C9H6FNO 2 [M+H]+ 180.0, found 180.0.

[000151] Step b: To a stirred solution of methyl 2-cyano-5-fluorobenzoate (3.85 g, 21.5 mmoles) in tetrahydrofuran (30 ml) and water (3 ml) at 0°C , lithium hydroxide monohydrate (1.11 g, 26.5 mmol) was added. The reaction was heated to rt and stirred for 1 h. Then, the solvent was evaporated and the residue was diluted with water (100 ml) and 2 M HCl (20 ml). The solid was collected by filtration and dried under vacuum to give the desired product. MS: (ES) m/z calculated for C8H4FNO2 [M+H]+166.0, found 166.0.

[000152] Step c: To a stirred solution of 2-cyano-5-fluorobenzoic acid (1.70 g, 10.3 mmol) in anhydrous tetrahydrofuran (105 ml) at -78°C, 1 .6 M methyl lithium solution in ether (25.74 ml, 41.2 mmoles) in drops. The mixture was stirred at -78 ° C for 1 h and was then slowly warmed to rt, quenched with saturated ammonium chloride, and extracted with ethyl acetate. The organic layer was purified by silica gel chromatography (0-100% ethyl acetate/hexane) to give 6-fluoro-3,3-dimethylisoindolin-1-one. MS: (ES) m/z calculated for C10H10FNO [M+H]+ 180.0, found 180.0.

[000153] Step d: A reaction flask containing 6-fluoro-3,3-dimethylisoindolin-1-one (620 mg, 3.46 mmol) in concentrated H2SO4 (1 ml) was cooled in an ice bath. A mixture of concentrated H2SO4 (1 ml) with 70% HNO3 (0.25 ml, 3.8 mmol) was added dropwise and the reaction mixture was stirred at 0°C for 2 h, then carefully quenched. with ice and diluted to 10 ml with cold water. The solid was filtered, washed with water and dried under vacuum to give the desired product 6-fluoro-3,3-dimethyl-7-nitroisoindolin-1-one. MS: (ES) m/z calculated for C10H9FN2O3 [M+H]+ 225.0, found 225.0.

[000154] Step e: To a solution of 6-fluoro-3,3-dimethyl-7-nitroisoindolin-1-one (0.56 g, 2.50 mmol) in ethanol (10 mL) and water (1 mL) at room temperature was added iron powder (0.58 g, 10.38 mmol) and ammonium chloride (1.90 g, 34.6 mmol). The reaction mixture was heated to 90 °C and stirred for 1 h. It was then cooled to room temperature, filtered through Celite, and rinsed with methanol (20 mL). The filtrate was concentrated to dryness, and the residue was diluted with ethyl acetate, washed with water, and brine. The combined organic layers were dried (Na2SO4), filtered, concentrated in vacuo, and purified by silica gel chromatography (0–100% ethyl acetate in hexanes) to provide the product 7-amino-6-fluoro-3,3-dimethylisoindolin-1-one. MS: (ES) m/z calculated for C10H11 FN2O [M+H]+195.1, found 195.1.

[000155] Step f: A mixture of 7-amino-6-fluoro-3,3-dimethylisoindolin-1-one (25 mg, 0.129 mmol), 3,4-dimethoxycyclobut-3-ene-1,2- dione (22.0 mg, 0.155 mmol, 1.2 equiv), and solution of HCl in dioxane (4 M, 32.3 ml) in anhydrous MeOH (0.65 ml) was stirred at 60 ° C for 18 hours. The solvents were removed to give the product which was directly used in the next step.

[000156] Step g: A 20 ml vial was charged with 3-((5-fluoro-1,1-dimethyl-3-oxoisoindolin-4-yl)amino)-4-methoxycyclobut-3-ene-1,2 -dione obtained above, followed by (1R)-1-(5-methyl-2-furyl)propan-1-amine tartrate salt (115.7 mg, 0.400 mmol) in methanol (0.5 ml) and triethylamine (101 mg, 1.00 mmol). The reaction mixture was stirred at 60°C for 18 hours. After gently blowing nitrogen over the reaction mixture to remove the solvent, the crude material was purified using reversed-phase HPLC using a mixture of water and acetonitrile as the eluent. (R)-3-((5-fluoro-1,1-dimethyl-3-oxoisoindolin-4-yl)amino)-4-((1-(5-methylfuran-2-yl)propylyl)amino) cyclobut-3-ene-1,2-dione was obtained. 1H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 8.81 (s, 1H), 8.28 (d, J = 9.1 Hz, 1H), 7.47 (dd , J = 11.0, 8.2 Hz, 1H), 7.41 (dd, J = 8.3, 3.9 Hz, 1H), 6.27 (d, J = 3.1 Hz, 1H) , 6.09 - 6.03 (m, 1H), 5.08 (m, 1H), 2.27 (s, 3H), 1.92 (m, 2H), 1.43 (s, 6H), 0.92 (t, J = 7.3 Hz, 3H). MS: (ES) m/z calculated for C22H22FN3O4 [M + Na]+ 434.1, found 434.4. Example 6: Synthesis of (R )-3-((5-fluoro-1,1,7-trimethyl-3-oxoisoindolin-4-yl)amino)-4-((1-(5-methylfuran-2-yl )propylyl)amino)cyclobut-3-ene-1,2-dione

[000157] Step a: To a solution of 7-amino-6-fluoro-3,3-dimethylisoindolin-1-one (150 mg, 0.77 mmol) in AcOH (2 ml) in a water bath, NIS (244 mg, 1.08 mmol) was added in portions at room temperature. The resulting mixture was stirred in a water bath for 30 minutes, quenched with water (1 ml) and extracted with ethyl acetate (10 ml). The organic layer was washed with brine (10 ml) and then dried over MgSO4. The solvent was evaporated under reduced pressure to give a brown solid, which was purified by silica gel chromatography (0-60% ethyl acetate in hexanes) to give 7-amino-6-fluoro-4-iodo-3,3- dimethylisoindolin-1-one. MS: (ES) m/z calculated for C10H10FIN2O [M+H]+ 321.0, found 321.0.

[000158] Step b: To a solution of 7-amino-6-fluoro-4-iodo-3,3-dimethylisoindolin-1-one (370 mg, 1.16 mmol) in dioxane (12 ml), CsF was added (705 mg, 4.64 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatririborinane (435 mg, 3.47 mmol) and [1,1'-bis (diphenylphosphine)ferrocene]dichloropalladium(II) (95 mg, 0.116 mmol). The resulting mixture was stirred at 80°C overnight. The reaction was divided between water (20 ml) and ethyl acetate (30 ml). The organic layer was washed with brine (20 ml) and then dried over MgSO4, filtered and concentrated to give the crude product, which was purified by silica gel chromatography (0-80% ethyl acetate in hexanes) to give 7-amino-6-fluoro-3,3,4-trimethylisoindolin-1-one. MS: (ES) m/z calculated for C11H13FN2O [M+H]+209.1, found 209.1.

[000159] Step c: A mixture of 7-amino-6-fluoro-3,3,4-trimethylisoindolin-1-one (40 mg, 0.192 mmol), 3,4-dimethoxycyclobut-3-ene-1,2-dione (32.8 mg, 0.231 mmol, 1.2 equiv), and HCl in dioxane solution (4 M, 48 μL) in anhydrous MeOH (1.0 mL) was stirred at 60 °C for 18 h. The solvents were removed to give the product which was directly used in the next step.

[000160] Step d: A 20 ml vial was charged with 3-((5-fluoro-1,1,7-trimethyl-3-oxoisoindolin-4-yl)amino)-4-methoxycyclobut-3-ene-1 ,2-dione obtained above, followed by (1R)-1-(5-methyl-2-furyl)propan-1-amine tartrate salt (222.7 mg, 0.77 mmol) in methanol (1.0 ml) and triethylamine (233 mg, 2.3 mmol). The reaction mixture was stirred at 60°C for 18 hours. After gently blowing nitrogen over the reaction mixture to remove the solvent, the crude material was purified using reversed-phase HPLC using a mixture of water and acetonitrile as the eluent. (R)-3-((5-fluoro-1,1,7-trimethyl-3-oxoisoindolin-4-yl)amino)-4-((1-(5-methylfuran-2-yl)propylyl)amino) cyclobut-3-ene-1,2-dione was obtained. 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.83 (s, 1H), 8.31 (d, J = 9.1 Hz, 1H), 7.29 (d , J = 12.0 Hz, 1H), 6.26 (d, J = 3.1 Hz, 1H), 6.12 - 6.02 (m, 1H), 5.08 (m, 1H), 2 .41 (s, 3H), 2.27 (s, 3H), 1.90 (m, 2H), 1.49 (s, 6H), 0.92 (t, J = 7.3 Hz, 3H) . MS: (ES) m/z calculated for C23H24FN3O4 [M + Na]+ 448.2, found 448.4. Example 7: Synthesis of (R)-2-(4-chloro-7-((2-((1-(5-methylfuran-2-yl)propylyl)amino)-3,4-dioxocyclobut-1-en acid -1-yl)amino)-1-oxoisoindolin-2-yl)-4-methoxybenzoic acid

[000161] Step a: A 1 liter round bottom flask containing 4-chloroisoindolin-1-one (25.0 g, 0.149 mol) in concentrated H2SO4 (50 ml) was cooled in an ice bath. A mixture of concentrated H2SO4 (50 ml) with 70% HNO3 (10 ml, 0.16 mol, 1.05 equiv.) was added dropwise and the reaction mixture was stirred at 0°C for 2 h, then , carefully cooled with ice and diluted to 1 liter with cold water. The solid was filtered, washed with water and dried under high vacuum to give 4-chloro-7-nitro-isoindolin-1-one. MS: (ES) m/z calculated for C8H5ClN2O3 [M-H]- 212.0, found 212.0.

[000162] Step b: To a stirred mixture of 4-chloro-7-nitro-isoindolin-1-one (23 g, 108 mmol) in ethanol at room temperature, iron powder (18.2 g, 324 mmol), followed by 4 M HCl in dioxane (162 ml, 648 mmol). The reaction mixture was stirred at room temperature for 1 h, then concentrated in vacuo. The residue was diluted with ethyl acetate and neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate (2 x 500 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to give 7-amino-4-chloro-isoindolin-1-one. MS: (ES) m/z calculated for C8H7ClN2O [M+H]+ 183.2, found 183.2.

[000163] Step c: To a reaction flask containing 7-amino-4-chloro-isoindolin-1-one (250 mg, 1.37 mmol) in dioxane (10 ml), methyl 2-bromo-5- was added. methoxy-benzoate (502 mg, 2.05 mmol), cesium carbonate (893 mg, 2.74 mmol), copper iodide (104 mg, 0.55 mmol) and (1S,2S)-N1,N2-dimethylcyclo -hexane-1,2-diamine (156 mg, 1.1 mmol). The mixture was purged with nitrogen then heated to 110°C. The reaction was stirred at 110°C for 1h and the reaction was monitored by LC-MS. Upon completion, the reaction was allowed to cool and was then filtered through Celite and rinsed with ethyl acetate. The crude product was purified by silica gel chromatography (0-50% ethyl acetate/hexane) to give methyl 2-(7-amino-4-chloro-1-oxo-isoindolin-2-yl)-5-methoxy- benzoate. MS: (ES) m/z calculated for C17H15ClN2O4[M+H]+347.1, found 347.1.

[000164] Step d: A mixture of methyl 2-(7-amino-4-chloro-1-oxo-isoindolin-2-yl)-5-methoxy-benzoate (160 mg, 0.46 mmol) and 3,4-dimethoxycyclobutane-1,2-dione (131 mg, 0.92 mmol) in anhydrous methanol (5 mL) was stirred at 60 °C overnight. The reaction mixture was evaporated and the residue was stirred in ethyl acetate (5 mL) at 50 °C for 30 min then allowed to cool to room temperature. The mixture was filtered and dried to give the product methyl 2-[4-chloro-7-[(2-methoxy-3,4-dioxo-cyclobutyl)amino]-1-oxo-isoindolin-2-yl]-5-methoxy-benzoate. EM: (ES) m/z calculated for C22H17ClN2O7 [M+H]+ 457.1, found 457.1.

[000165] Step e: A methyl 2-(4-chloro-7-((2-methoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-1-oxoisoindolin-2-yl)-4 -methoxybenzoate (60 mg, 0.12 mmol), (R)-1-(5-methylfuran-2-yl)propan-1-amine (22 mg, 0.15 mmol) in methanol (5 ml) was added to the room temperature. The reaction mixture was stirred overnight at 60°C and then concentrated. The residue was diluted with dichloromethane and washed with water. The organic layer was concentrated. To the residue, THF (5 ml), water (1 ml), and LiOH (large excess) were added. The reaction mixture was stirred at room temperature for 1 h and 60°C for 2 h. Aqueous HCl (1N) and dichloromethane were added and the combined organic layer was concentrated. THF was added and the mixture was filtered to get rid of the solid. The residue was purified by reversed-phase HPLC using a mixture of water and acetonitrile as the eluent. (R)-2-(4-chloro-7-((2-((1-(5-methylfuran-2-yl)propylyl)amino)-3,4-dioxocyclobut-1-en-1-yl) acid amino)-1-oxoisoindolin-2-yl)-4-methoxybenzoic acid was obtained. 1H NMR (400 MHz, Methanol-d4) δ 8.12 - 8.03 (m, 2H), 7.59 (d, J = 8.8 Hz, 1H), 7.15 - 7.02 (m, 2H), 6.20 (s, 1H), 5.94 (s, 1H), 5.20 - 4.80 (m, 3H), 3.90 (s, 3H), 2.24 (s, 3H ), 2.03 - 1.85 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H). MS: (ES) m/z calculated for C28H24ClN3O7 [M + H]+ 550.1, found 550.3. Example 8: Synthesis of (R)-3-((5-fluoro-3-oxoisoindolin-4-yl)amino)-4- ((1 -(5-methylfuran-2-yl)propyl-1-d)amino )cyclobut-3-ene-1,2-dione

[000166] Step a: To a 40 ml vial, (R)-2-methylpropane-2-sulfinamide (1.83 g, 15.1 mmoles), 1-(5-methylfuran-2-yl)propan was added -1-one (2.0 ml, 15.1 mmoles) and titanium ethoxide (7.8 ml). The reaction mixture was stirred at 60oC overnight. The reaction was diluted with dichloromethane (100 ml) and cooled quickly with sodium sulfate decahydrate (10.2 g). The reaction mixture was filtered through celite and rinsed with dichloromethane. Evaporation of the solvent gave the crude product which was purified by silica gel chromatography using a mixture of ethyl acetate and hexane as the eluent.

[000167] Step b: To a mixture of the product from the previous step (1122 mg, 4.65 mmoles), THF (17.5 ml) and D2O (0.36 ml) at -55oC, sodium borodeuteride (575 mg, 13.7 mmoles). The reaction mixture was stirred at the same temperature for 3 h. After gently blowing nitrogen over the reaction mixture to remove the solvent, dichloromethane was added. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography using a mixture of dichloromethane and methyl tert-butyl ether as the eluent.

[000168] Step c: The product from the previous step (422 mg, 1.73 mmol) was dissolved in MeOH (5 ml) at 0oC, and acetyl chloride (400 μL) was added. The reaction was stirred for 1 h. After gently blowing nitrogen over the reaction mixture to remove the solvent, a mixture of methyl tert-butyl ether and water was added. The aqueous layer was collected and basified with sodium carbonate solution (2 M). The mixture was extracted with CHCl3 (3x). The combined organic layers were dried over Na2SO4, filtered and concentrated to give the product.

[000169] Step d: A 3-((5-fluoro-3-oxoisoindolin-4-yl)amino)-4-methoxy-cyclobut-3-ene-1,2-dione (41.4 mg, 0.150 mmol) , (R)-1-(5-methylfuran-2-yl)propan-1-d-1-amine (31.9 mg, 0.228 mmol) in methanol (1 ml) was added at room temperature. The reaction mixture was stirred overnight at 45°C. After gently blowing nitrogen over the reaction mixture to remove the solvent, a mixture of aqueous HCl (1N) and dichloromethane was added. The mixture was filtered and the residue was purified by preparative TLC using ethyl acetate as the eluent. (R)-3-((5-fluoro-3-oxoisoindolin-4-yl)amino)-4-((1-(5-methylfuran-2-yl)propyl-1-d)amino)cyclobut-3- ene-1,2-dione was obtained. 1H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1H), 8.70 (s, 1H), 8.25 (s, 1H), 7.46 (dd, J = 11.2, 8.2 Hz, 1H), 7.33 (dd, J = 8.2, 3.7 Hz, 1H), 6.25 (d, J = 3.1 Hz, 1H), 6.06 - 6, 03 (m, 1H), 4.32 (s, 2H), 2.26 (s, 3H), 2.00 - 1.80 (m, 2H), 0.90 (t, J = 7.3 Hz , 3H). MS: (ES) m/z calculated for C20DH17FN3O4 [M + H]+ 385.1, found 385.4. Example 9: Synthesis of (R)-3-((5-fluoro-3-oxoisoindolin-4-yl)amino)-4- ((1-(5-methyloxazol-2-yl)propylyl)amino)cyclobut-3 -ene-1,2-dione

[000170] Step a: To a 40 ml vial, (R)-2-((tert-butoxycarbonyl)amino)butanoic acid (1.00 g, 4.92 mmoles), 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo [4,5-b]pyridinium (HATU, 1.96 g, 5.16 mmol), DMF (6 ml) and triethylamine (1.51 ml). The reaction mixture was stirred for 2 min and prop-2-yn-1-amine (378 μL, 5.90 mmol) was added. The reaction mixture was further stirred at room temperature for 2 h. The reaction mixture was diluted with water and diethyl ether and extracted with diethyl ether (6x). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography using a mixture of ethyl acetate and dichloromethane as the eluent.

[000171] Step b: To a 40 ml flask, auric chloride (128 mg, 0.424 mmol), acetonitrile (10 ml), and the product from the previous step (501 mg, 2.09 mmol) were added. The reaction mixture was stirred at 50oC overnight. After gently blowing nitrogen over the reaction mixture to remove the solvent, a mixture of saturated ammonium chloride solution and methyl tert-butyl ether was added. The mixture was extracted with methyl tert-butyl ether (3x). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography using a mixture of ethyl acetate and hexane as the eluent.

[000172] Step c: To a stirred solution of the product from the previous step (301 mg, 1.25 mmol) in dichloromethane (1 ml), 4N HCl in dioxane (1 ml) was added. The mixture was stirred at room temperature overnight. After gently blowing nitrogen over the reaction mixture to remove the solvent, a mixture of water and hexane was added. The aqueous layer was collected and basified with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (3x) and chloroform/isopropanol (2/1, v/v) (2x). The combined organic layers were dried over Na2SO4, filtered and concentrated to give the product.

[000173] Step d: A 3-((5-fluoro-3-oxoisoindolin-4-yl)amino)-4-methoxy-cyclobut-3-ene-1,2-dione (42.4 mg, 0.154 mmol) , (R)-1-(5-methyloxazol-2-yl)propan-1-amine (25.9 mg, 0.185 mmol) in methanol (0.5 ml) was added at room temperature. The reaction mixture was stirred overnight at 50°C. After gently blowing nitrogen over the reaction mixture to remove the solvent, a mixture of aqueous HCl (1N) and dichloromethane was added. The mixture was filtered and the residue was purified by preparative TLC using a mixture of dichloromethane and acetonitrile (1/1, v/v) as the eluent. (R)-3-((5-fluoro-3-oxoisoindolin-4-yl)amino)-4-((1-(5-methyloxazol-2-yl)propylyl)amino)cyclobut-3-ene-1, 2- dione was obtained. 1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.73 (s, 1H), 8.48 (d, J = 7.5 Hz, 1H), 7.49 (dd , J = 11.2, 8.2 Hz, 1H), 7.36 (dd, J = 8.3, 3.8 Hz, 1H), 6.87 (d, J = 1.4 Hz, 1H) , 5.33 - 5.20 (m, 1H), 4.34 (s, 2H), 2.32 (d, J = 1.2 Hz, 3H), 2.09 - 1.87 (m, 2H ), 0.93 (t, J = 7.4 Hz, 3H). MS: (ES) m/z calculated for C19H17FN4O4 [M + H]+ 385.1, found 385.4. Example 10: Synthesis of (R )-2-(4-chloro-7-((2-((1-(5-methylfuran-2-yl)propylyl)amino)-3,4-dioxocyclobut-1- en-1-yl)amino)-1-oxoisoindolin-2-yl)acetamide

[000174] Step a: A 4-liter Erlenmeyer flask containing 3-chloro-2-methyl-benzoic acid (100.0 g, 0.586 mole) in concentrated H2SO4 (500 ml) was cooled in an ice bath. 70% HNO3 (45.2 ml, 0.703 mole, 1.2 equiv.) was added dropwise and the reaction mixture was stirred at 0°C for 2 h, then carefully quenched with ice and diluted to 4 L with cold water. A white solid was filtered, washed with water and dried under high vacuum to give a mixture of 3-chloro-2-methyl-6-nitro-benzoic acid and 3-chloro-2-methyl-5-nitro-benzoic acid in ratio 3:1. MS: (ES) m/z calculated for C8H5ClNO4 [M-H]- 214.0, found 214.0.

[000175] Step b: The mixture of isomeric acids from the previous step (50 g, 232.0 mmol) was dissolved in anhydrous DMF (200 ml), anhydrous Na2CO3 (27.0 g, 255.2 mmol, 1.1 equiv .) was added and the reaction was stirred at room temperature for 30 minutes. Methyl iodide (15.9 ml, 255.2 mmoles, 1.1 equiv.) was added and stirring continued at room temperature for 3 h. The reaction mixture was diluted with water (1.2 L) and the product was extracted using Et2O (3 x 250 ml). The combined organic layers were washed with brine (4 x 100 ml), dried over MgSO4, filtered and evaporated to give the product.

[000176] Step c: The mixture of isomeric esters from the previous step (49.7 g, 216.5 mmoles) was dissolved in CCl4 (400 ml) and N-bromosuccinimide (57.8 g, 324.7 mmoles, 1.5 equiv.) was added followed by benzoyl peroxide (10.4 g, 43.2 mmol, 0.20 equiv). The reaction mixture was stirred under reflux overnight, then cooled to room temperature and filtered. The filtrate was evaporated and the residue was purified by silica gel chromatography (100:0 to 9:1 Hex:EtOAc) to give the product as a single isomer. 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 9.2 Hz, 1H), 7.65 (d, J = 9.2 Hz, 1H), 4.63 (s, 2H), 4.01 (s, 3H).

[000177] Step d: A mixture of the product from the previous step (316 mg, 1.02 mmol), 2-aminoacetamide hydrochloride (171 mg, 1.55 mmol) and triethylamine (427 μL, 3.06 mmol) in ethanol (2 ml) was stirred at room temperature overnight. After gently blowing nitrogen over the reaction mixture to remove the solvent, a mixture of aqueous HCl (1N) and water was added. The mixture was filtered and the residue was rinsed with aqueous HCl (1N) and water to give the desired product.

[000178] Step e: To a stirred mixture of the product from the previous step (249 mg, 0.925 mmol) in ethanol (1 ml) at room temperature, iron powder (158 mg, 2.68 mmol) was added, followed by 4 M HCl in dioxane (0.46 ml, 1.84 mmol). The reaction mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate solution was added and the mixture was diluted with methanol. The mixture was filtered through celite and rinsed with methanol. The filtrate was concentrated to remove methanol and subsequently extracted with dichloromethane. The combined organic layers were concentrated to generate the desired product.

[000179] Step f: A mixture of the product from the previous step (131 mg, 0.55 mmol) and 3,4-dimethoxycyclobutane-1,2-dione (118 mg, 0.83 mmol) in anhydrous methanol (2 ml) was stirred at 60°C overnight. After gently blowing nitrogen over the reaction mixture to remove the solvent, ethyl acetate was added. The mixture was filtered, rinsed with ethyl acetate and dried to give the product.

[000180] Step g: A 2-(4-chloro-7-((2-methoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-1-oxoisoindolin-2-yl)acetamide (39 .9 mg, 0.114 mmol), (R)-1-(5-methylfuran-2-yl)propan-1-amine (23.0 mg, 0.165 mmol) in ethanol (1 ml) was added at room temperature . The reaction mixture was stirred overnight at 65°C. After gently blowing nitrogen over the reaction mixture to remove the solvent, a mixture of aqueous HCl (1N) and dichloromethane was added. The mixture was filtered and the residue was rinsed with water, dichloromethane and methyl tert-butyl ether. (R)-2-(4-chloro-7-((2-((1-(5-methylfuran-2-yl)propylyl)amino)-3,4-dioxo-cyclobut-1-en-1-yl )amino)-1-oxoisoindolin-2-yl)acetamide was obtained. 1H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 9.12 (d, J = 8.9 Hz, 1H), 7.67 - 7.52 (m, 3H), 7 .27 - 7.18 (m, 1H), 6.25 (d, J = 3.1 Hz, 1H), 6.06 - 6.02 (m, 1H), 5.18 - 5.08 (m , 1H), 4.48 (s, 2H), 4.11 (s, 2H), 2.25 (s, 3H), 2.01 - 1.80 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H). MS: (ES) m/z calculated for C22H21ClN4O5 [M + Na]+ 479.1, found 479.0.

[000181] The following compounds were produced using similar synthetic methods as described here with appropriate reagents and were characterized by MS (mass spectrometry) and NMR as illustrated in Table 1. Table 1. Characterization of compounds

Biological Example 1: Ligand binding assay for CXCR2 activity

[000182] A ligand binding assay can be used to determine the ability of potential CXCR2 antagonists to block the interaction between CXCR2 and any of its ligands. HEK-293 cells stably expressing CXCR2 or human neutrophils expressing CXCR2 are centrifuged and resuspended in assay buffer (20 mM HEPES pH 7.1, 140 mM NaCl, 1 mM CaCl2, 5 mM MgCl2 , 0.1% sodium azide with 0.1% bovine serum albumin) to a concentration of 5 x 105 cells/ml. Binding assays are set up as follows: compounds for screening are diluted to a maximum of 20 μM, and 0.1 ml of cells containing 5 x 104 cells (for HEK-293 cells) or 3 x 104 cells (for human neutrophils) are added to each compound-containing well. Next, 0.1 mL of 125I-labeled CXCL8 (obtained from PerkinElmer; Waltham, MA) diluted in assay buffer to a final concentration of ~50 pM, yielding ~1μCi per well is added, and the plates are sealed and incubated. for approximately 3 hours at 25°C on a shaking platform. Reactions are aspirated onto GF/B glass filters pre-soaked in 0.3% polyethyleneimine (PEI) solution in a vacuum cell harvester (Packard Instruments; Meriden, CT). Scintillation fluid (50 μL; Microscint 20, Packard Instruments) is added to each well, the plates are sealed, and radioactivity is measured in a Top Count scintillation counter (Packard Instruments). Control wells containing only diluent (for total counts) or 20 μM compound are used to calculate the percentage of total inhibition for compound. The Prisma computer program from GraphPad, Inc. (San Diego, California) can be used to calculate IC50 values. IC50 values are those concentrations necessary to reduce binding of labeled CXCR8 to the receptor by 50%. Compounds in Figure 1 having an IC50 value in the binding assay less than 100 nM are labeled (+++); 100-1000 nM are labeled (++); and less than or equal to 20 μM, but above 1000 nM, are labeled (+).

Biological Example 2: Migration/Chemotaxis Assay

[000183] A serum chemotaxis assay can be used to determine the effectiveness of potential receptor antagonists in blocking migration mediated through chemokine receptors, such as CXCR2. This assay is routinely performed using the ChemoTX® microchamber system with a 5μm pore size polycarbonate membrane. To initiate such an assay, cells expressing the chemokine receptor (in this case, neutrophils isolated from human whole blood) are collected by centrifugation at 400 x g at room temperature, then suspended at 4 million/ml in human serum. The compound being tested is serially diluted from a maximum final concentration of 10μM (or an equivalent volume of its solvent (DMSO)) and is then added to the cell/serum mixture. Separately, recombinant human CXCL5 (ENA-78) and its EC50 concentration (10nM) is placed in the lower wells of the ChemoTX® plate. The 5 μm (pore size) polycarbonate membrane is placed on the plate, and 20 μl of the cell/compound mixture is transferred to each well of the membrane. The plates are incubated at 37°C for 45 minutes, after which the polycarbonate membranes are removed and 5 μl of CyQUANT DNA intercalating agent (Invitrogen, Carlsbad, CA) is added to the bottom wells. The amount of fluorescence, corresponding to the number of migrated cells, is measured using a Spectrafluor Plus plate reader (TECAN, San Jose, CA).

[000184] Particular embodiments of the present invention are described here, including the best way known to the inventors to carry out the invention. Upon reading the above description, variations of the disclosed embodiments may become apparent to individuals working in the art, and it is expected that those skilled in the art may employ such variations as appropriate. Accordingly, it is intended that the invention be practiced other than as specifically described herein, and that the invention includes all modifications and equivalents of the subject matter mentioned in the claims appended hereto, as permitted by applicable law. Furthermore, any combination of the above-described elements in all their possible variations is encompassed by the invention unless otherwise indicated here or clearly contradicted by the context.

[000185] All publications, patent applications, accession numbers and other references cited in this specification are incorporated herein by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.

Claims (18)

1. Compound, characterized by the fact that it presents Formula (I): R1 and R2 are each independently selected members of the group consisting of H, halogen, CN, C1-4 alkyl, C1-4 alkoxy and C1-4 haloalkyl; R3a is a member selected from the group consisting of methyl, ethyl, propyl, isopropyl, trifluoromethyl, CH2CF3 and CF2CF3; R3b is a selected member of the group consisting of H and D; R4 is a member selected from the group consisting of H, C1-8 alkyl, -Y and C1-4alkylene-Y; wherein Y is aryl or heteroaryl, and each R4 is optionally substituted by one to four substituents selected from the group consisting of halogen, -CN, -CO2Ra, -CONRaRb, -C(O)Ra, -OC(O)NRaRb , NRaC(O)Rb, -NRaC(O)2Rc, -NRaC (O)NRaRb, -NRaRb, -ORa, -S(O)2NRaRb, -NRaS(O)2Rb and -Rc, where each Ra and Rb is independently selected from hydrogen, C1-4 alkyl, C1-4 hydroxyalkyl and C1-4 haloalkyl, and Rc is selected from C1-4 alkyl, C1-4 hydroxyalkyl and C1-4 haloalkyl; R5a and R5b are each independently selected members of the group consisting of H, halogen, C1-4 alkyl, C1-4 alkoxy and CN; R6a and R6b are each independently selected members of the group consisting of H, C1-4 alkyl, C1-4 hydroxyalkyl and C1-4 haloalkyl or, optionally, R6a and R6b are taken together to form oxo (= O); X is CH or N; or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, characterized in that R3a is ethyl or isopropyl. 3. Compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that R3b is H. 4. Compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that R3b is D. 5. Compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, characterized by the fact that R1 is methyl. 6. Compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, characterized by the fact that X is CH. 7. Compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, characterized by the fact that X is N. 8. Compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, characterized by the fact that each of R5a and R5b is independently selected from the group consisting of H, Cl and F . 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein each of R6a and R6b is independently selected from the group consisting of H and C1-4 alkyl. 10. Compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, characterized by the fact that R4 is C1-8 alkyl, optionally substituted with -halogen, -CN, -CO2Ra, -CONRaRb, -C(O)Ra, -OC(O)NRaRb, -NRaC (O)Rb, -NRaC(O)2Rc, -NRaC(O)NRaRb, -NRaRb, -ORa, -S(O)2NRaRb , and -NRaS(O)2Rb. 11. Compound according to claim 1, characterized by the fact that it has Formula (Ia), in which: R1 is selected from the group consisting of Cl and CH3; R3b is selected from the group consisting of H and D; R4 is a member selected from the group consisting of H and C1-8 alkyl, in which the C1-8 alkyl is optionally substituted by -CONRaRb, -OC(O)NRaRb, -NRaC(O)Rb, -NRaC(O) 2Rc, -NRaRb, and -ORa, wherein each Ra and Rb is independently selected from hydrogen, C1-4 alkyl, C1-4 hydroxyalkyl, and C1-4 haloalkyl, and Rc is selected from C1-4 alkyl, C1- 4 hydroxyalkyl and C1-4 haloalkyl; R5a and R5b are each independently selected members of the group consisting of H, F, Cl and CH3; R6a and R6b are each independently selected members of the group consisting of H, C1-4 alkyl, C1-4 hydroxyalkyl and C1-4 haloalkyl; or, optionally, R6a and R6b are taken together to form oxo (=O); or a pharmaceutically acceptable salt thereof, optionally, wherein (1) R3b is H; R4 is H or CH3; R5a is H, F or Cl; R5b is H, F, Cl; R6a and R6b are independently selected from the group consisting of H and CH3, or are taken together to form oxo (=O); or (11) R3b is D; R4 is H or CH3; R5a is H, F or Cl; R5b is H, F, Cl; R6a and R6b are independently selected from the group consisting of H and CH3, or are taken together to form oxo (=O). 12. Compound according to claim 1, characterized by the fact that it presents Formula (Ib), in which: R1 is selected from the group consisting of Cl and CH3; R3b is selected from the group consisting of H and D; R4 is a member selected from the group consisting of H and C1-8 alkyl, in which the C1-8 alkyl is optionally substituted by -CONRaRb, -OC(O)NRaRb, -NRaC(O)Rb, -NRaC(O) 2Rc, -NRaRb, and -ORa, wherein each Ra and Rb is independently selected from hydrogen, C1-4 alkyl, C1-4 hydroxyalkyl, and C1-4 haloalkyl, and Rc is selected from C1-4 alkyl, C1- 4 hydroxyalkyl and C1-4 haloalkyl; R5a and R5b are each independently selected members of the group consisting of H, F, Cl and CH3; R6a and R6b are each independently selected members of the group consisting of H, C1-4 alkyl, C1-4 hydroxyalkyl and C1-4 haloalkyl; or, optionally, R6a and R6b are taken together to form oxo (=O); or a pharmaceutically acceptable salt thereof, optionally, wherein (i) R3b is H; R4 is H or CH3; R5a is H, F or Cl; R5b is H, F, Cl; R6a and R6b are independently selected from the group consisting of H and CH3, or are taken together to form oxo (=O); or (ii) R3b is D; R4 is H or CH3; R5a is H, F or Cl; R5b is H, F, Cl; R6a and R6b are independently selected from the group consisting of H and CH3, or are taken together to form oxo (=O). 13. Compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of: 14. Compound according to claim 1, characterized by the fact that it has the Formula or a pharmaceutically acceptable salt thereof. 15. Compound according to claim 1, characterized by the fact that it has the Formula or a pharmaceutically acceptable salt thereof. 16. Compound according to claim 1, characterized by the fact that it has the Formula or a pharmaceutically acceptable salt thereof. 17. Compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, characterized by the fact that it is for use in the treatment of a CXCR2-mediated condition or disease. 18. Compound according to claim 17, characterized by the fact that the CXCR2-mediated disease is selected from the group consisting of psoriasis, rheumatoid arthritis, radiation-induced fibrotic lung disease, autoimmune bullous dermatitis (AIBD), lung disease chronic obstructive and ozone-induced airway inflammation, and cancer selected from the group consisting of rhabdomyosarcoma, Lewis lung carcinoma (LLC), non-small cell lung cancer, esophageal squamous cell carcinoma, esophageal adenocarcinoma, renal cell carcinoma (RCC), colorectal cancer (CRC), acute myeloid leukemia (AML), breast cancer, gastric cancer, prostatic small cell neuroendocrine carcinoma (SCNC), liver cancer, glioblastoma, liver cancer, oral carcinoma squamous cell carcinoma, head and neck squamous cell carcinoma, pancreatic cancer, papillary thyroid cancer, intrahepatic cholangiocellular carcinoma, hepatocellular carcinoma, bone cancer and nasopharyngeal carcinoma.